Small Molecule Kinase Inhibitors for the Treatment of Brain Cancer

Perspective pubs.acs.org/jmc

Small Molecule Kinase Inhibitors for the Treatment of Brain Cancer Timothy P. Heffron* Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States S Supporting Information *

ABSTRACT: In addition to each of the factors that govern the identification of a successful oncology drug candidate, drug discovery aimed at treating neurological cancer must also consider the presence of the blood−brain barrier (BBB). The high level of expression of efflux transporters (e.g., P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp)) at the BBB limits many small molecules from freely reaching the brain, where neurooncologic malignancies reside. Furthermore, many of the targets identified for the potential treatment of central nervous system (CNS) malignancies suggest that kinase inhibitors, capable of penetrating the BBB to reach their target, would be desirable. This Perspective discusses the unmet need for neurooncology treatments, the appeal of kinase targets in this space, and a summary of what is known about free brain penetration of clinical inhibitors of kinases that are of interest for the treatment of brain cancer.

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BACKGROUND Neurooncology encompasses the study of tumors that originate in the brain (e.g., glioblastoma multiforme (GBM)) as well as brain metastases. In 2015, it was anticipated that more than 21 000 new cases of malignant brain and central nervous system (CNS) cancers would be diagnosed in the United States that year.1 Among malignant brain tumors, the most common is GBM which has an associated poor prognosis (3-year survival rate 3−5%).2 Despite the apparent unmet medical need, there has been little progress in developing new treatments for GBM. Most evaluations of chemotherapeutics in GBM have failed. Currently, the alkylating agents temozolomide (approved 2005) and the carmustine-based Gliadel wafer (approved 1996) are the only chemotherapeutics that are FDA approved for the treatment of newly diagnosed GBM. Other neurological cancers have similarly limited drug treatment options. In addition to the need for more treatment options for primary brain tumors, metastasis of tumors to the CNS occurs from as many as 40% of peripheral tumors, with well over 100 000 cases per year.3 When a kinase inhibitor is used for the treatment of peripheral disease, such CNS metastasis is a risk as a mechanism of emergent resistance if that inhibitor is not freely CNS penetrant. In this scenario, treatment of a tumor with drug is effective until disease progression occurs in the CNS, where drug concentrations are limited. As an example of the significance of the challenge presented by resistance due to CNS metastases, 14% of patients with HER2-positive breast cancer treated with pertuzumab had first evidence of disease progression due to CNS metastasis, evidently as a result of the inability of pertuzumab to cross the blood−brain barrier (BBB).4 Unfortunately, as discussed below, this scenario is not limited to HER2-positive disease treated with a therapeutic antibody but also happens with numerous FDA approved small molecule kinase inhibitors that do not penetrate the CNS. © 2016 American Chemical Society

For CNS metastases, prognosis is generally poor and chemotherapy is useful only in limited settings,5 furthering the unmet need for new chemotherapeutics for malignancy in the CNS. While primary brain tumors and brain metastases are distinct disease manifestations and may require targeting different drivers of disease, for the medicinal chemist, the approach to treating each of these indications requires the same considerations of the BBB, which typically limits small molecule penetration to the CNS where brain tumors reside. Furthermore, for both primary and secondary brain tumors there is biological rationale to develop BBB penetrating kinase inhibitors. While there have been 32 kinase inhibitors approved for the treatment of cancers that reside outside the CNS, no kinase inhibitor has been approved for the treatment of primary CNS tumors, while alectinib (61) has recently received accelerated approval to treat patients including those with brain metastases. One reason for the lack of approved kinase inhibitors for treating brain tumors is that in order to effectively treat brain tumors, the kinase inhibitor must be capable of reaching its target. Therefore, the kinase inhibitor must effectively cross the BBB. As will be discussed below (and included as Supporting Information), the majority of approved kinase inhibitors and kinase inhibitors that have advanced to clinical study have no report of CNS penetration, reportedly limited CNS penetration, or CNS penetration that is expected to be limited due to the action of the efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp). When considering potential therapeutics for the treatment of brain cancer, it is frequently asserted that because of disruption of the BBB by primary tumors or metastases in the brain, Received: April 21, 2016 Published: July 14, 2016 10030

DOI: 10.1021/acs.jmedchem.6b00618 J. Med. Chem. 2016, 59, 10030−10066

Journal of Medicinal Chemistry

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molecules are not strong substrates of P-gp or Bcrp, efflux transporters highly expressed at the BBB.8,10 Small molecules that are significant substrates of P-gp are anticipated to have limited free CNS penetration, and in the discussion of clinical kinase inhibitors below, molecules that are reported to be P-gp substrates are suggested to likely have limited CNS penetration. For medicinal chemists interested in kinase inhibitors to treat brain cancer, avoidance of P-gp transport must be a focus so as to maximize Kp,uu. Considerations in the design of kinase inhibitors (or any small molecule) to limit transporter mediated efflux include a number of physicochemical properties that can be prospectively calculated. Among the most critical properties to consider are the reported correlations between topological polar surface area (TPSA) and/or the number of hydrogen bond donors (HBD) and the likelihood of P-gp mediated efflux.8 ATP-competitive small molecule kinase inhibitors generally employ hydrogen bonding interactions with the hinge of the kinase, and oftentimes multiple hydrogen bond donors are utilized.11 As a result of the common use of frequent hydrogen bond donors within kinase inhibitors, overcoming the physicochemical property restraints that predict efflux while maintaining other desirable attributes of kinase inhibitors, including potency, is a challenge. Indeed, a comparison of the median values of physicochemical properties of 119 CNS approved drugs12 with those for the 34 kinase inhibitors approved for clinical use (all indications) reveals significant disparities (Table 1). Whereas CNS drugs have a median value of 1 HBD,

consideration of the BBB is not relevant. However, while it may be true that a tumor can disrupt the BBB, it generally does so just partially and significant literature reports indicate the importance of the BBB in limiting drug penetration to its intended target even when a tumor causes such partial disruption.6 Additionally, GBM in particular is noted to grow in a diffuse manner in which a significant portion of the tumor grows behind an intact BBB, and so without effective drugs that are capable of freely crossing that barrier the tumor progresses.7 That GBM grows in such a manner so as to remain behind an intact BBB punctuates the need for small molecules to be able to penetrate that barrier if they are to have potential to effectively treat that disease. With an understanding of the importance of free BBB penetration for drugs targeting brain cancer, neurooncology medicinal chemistry programs have much in common with programs for other CNS diseases. Fortunately, in recent years there has been a much improved appreciation for the requirement to achieve sufficient free drug concentration in the brain, if that is where the target resides. A recent Perspective provides an excellent review of the concepts of free brain penetration that are essential to CNS and neurooncology programs alike and pertinent to the remainder of the discussion within.8 Succinctly, it is important to note that it is critical that kinase inhibitors that are intended to treat brain tumors achieve therapeutically beneficial f ree drug concentrations in the brain. Indeed, a recent conference on CNS cancer drug discovery and development emphasized the need for neurooncology programs to focus on achieving free brain penetration.9 To assess in preclinical studies whether effective therapeutic concentrations of a molecule cross the BBB, and therefore whether it has a realistic chance of achieving efficacy by the intended mechanism, some assessment of free brain or, as a surrogate, cerebral spinal fluid (CSF) concentrations is needed.8 To assess the extent to which a small molecule freely penetrates the BBB (as opposed to just achieving a target free concentration in the brain), a comparison of free brain or CSF concentrations to free plasma concentrations is needed (Kp,uu). It is worth noting here that in the discussion of free brain penetration of clinical kinase inhibitors found below, the target therapeutic concentration is not often available, and so an assessment of free CNS penetration (Kp,uu or free brain-to-free plasma concentration ratios), where available, is utilized for an assessment. Where such values were available, we considered values of 0.3 demonstrate a significant degree of free CNS penetration. In principle, therapeutic free concentration of drug might be able to penetrate the BBB even with very low Kp,uu values. In order for this to occur, however, there would need to be a corresponding increase in systemic exposure that might increase risk of unintended side effects. To illustrate, a kinase inhibitor with a Kp,uu of 0.1 would require 10 times the sytemic exposure to achieve a therapeutic benefit in the brain compared to a kinase inhibitor equivalent in all aspects except for a Kp,uu of 1.0. When targeting CNS disease, then, the importance of maximizing Kp,uu is a significant consideration and likely to impact the safety/tolerability of a molecule at doses required to achieve therapeutically beneficial free concentrations in the CNS. With an understanding of the importance of achieving free CNS penetration with molecules intended for the treatment of brain cancers, a paramount requirement for achieving significant free drug concentrations behind the BBB is that the small

Table 1. Comparison of Median Values of Physicochemical Properties for Kinase Inhibitors Approved for Clinical Use and 119 Drugs Approved for CNS Indications

a b

median property value

approved kinase inhibitors (n = 34)a

CNS drugs (n = 119)b

cLogP cLogD7.4 TPSA (Å2) HBD MW pKa

4.2 3.6 91 2 483 7.0

2.8 1.7 45 1 305 8.4

Kinase inhibitors approved for any indication through 2015.13 Marketed CNS drugs. Values obtained from ref 12.

approved kinase inhibitors have 2. Additionally, approved kinase inhibitors have a median TPSA value double that of approved CNS drugs. Kinase inhibitors also tend to have significantly higher MW and lipophilicity than CNS drugs. For more than 30 years, kinase inhibitors have been the focus of significant pharmaceutical pursuit and the appeal of kinase inhibitors as potential therapeutics extends to the treatment of brain tumors and metastases.14 While the nature of kinase inhibitors, particularly ATP competitive versions, may have some constraints on physical properties to achieve potency that are contrary to what is typical for CNS drugs, realizing potent kinase inhibitors that are capable of significant free brain penetration is possible. However, free brain penetration has not been a design consideration for many kinase inhibitor programs and in some cases may have been intentionally avoided.15 Even when intentionally seeking potent and freely BBB penetrant kinase inhibitors, there are, of course, limitations to available in vivo brain cancer disease models in which such molecules can be studied and none “fully reflects human 10031



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Table 2. Structures and Key Properties for VEGFR and PDGFR Inhibitors Advanced to Clinical Study for Brain Cancera

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Table 2. continued

a

Properties for 119 marketed CNS drugs are included for comparison. *Median value of 119 marketed CNS drugs.12

gliomas.”16 As an example, the U87 model of glioblastoma is a frequently studied GBM model used in orthotopic mouse xenograft studies. The use of the U87 model to assess whether or not a molecule has potential in the treatment of brain cancer is limited, however, as it is known to maintain a highly disrupted BBB, not relevant to clinical disease, and not to grow in the diffuse manner observed in human patients in which the tumor invades healthy brain with an intact BBB.17 For this reason, the U87 and potentially other models may overestimate the likelihood that an agent may provide therapeutic benefit in human GBM patients. To understand whether the drug is capable of reaching its target in brain tissue, an evaluation of free brain-to-plasma ratios, free brain concentrations, change in brain concentration between wild-type mice and transporter knockout mice, or at least assessment of whether it is a substrate of P-gp or Bcrp is desirable. The basis for the interest in kinase inhibitors to treat brain tumors begins with the underlying biology of CNS malignancy. In the following sections, individual kinase targets with relevance in CNS malignancy are introduced. In many cases kinase inhibitors have been studied in clinical trials of patients with brain tumors or metastases without success. However, in many of those cases limited CNS penetration of the kinase inhibitor may have contributed to a lack of efficacy. We identify clinical kinase inhibitors for the kinase targets, and within each section on a given kinase target, available data related to brain penetration of any clinical inhibitors of that target are summarized. In the few cases where BBB penetrating inhibitors of a kinase target for brain cancer are reported, the medicinal chemistry efforts leading to this profile are discussed. Ultimately, we summarize whether or not clinical brain penetrant inhibitors of kinase targets of interest for neurooncology are available. Finally, a comparison of the physical properties of clinical CNS penetrant kinase inhibitors for brain cancer with those that have limited CNS penetration reveals remarkable similarity, and disparity from properties of CNS drugs.

its high expression in this context.20 Indeed, at least 14 inhibitors of VEGFR and/or PDGFR have been evaluated for their potential in the treatment of CNS tumors (Table 2), yet an unfortunate few would be expected to freely penetrate the BBB to reach such tumors. Cediranib (1, Table 2)21 and pazopanib (2, Table 2)22 have been studied in phase II and phase III trials in GBM patients but did not show a survival benefit.23,24 The diffuse nature of GBM vasculature growth would require effective penetration of brain tissue by the inhibitors to maximize efficacy. However, both cediranib and pazopanib have been reported to be substrates of both P-gp and Bcrp in vitro and these transporters were found to limit brain exposure in mice.25,26 Like cediranib and pazopanib, sunitinib (3),27 sorafenib (4),28 nintedanib (5),29 tivozanib (6),30 and dovitinib (7)31 were each ineffective in clinical GBM studies.32−36 Sunitinib, sorafenib, and nintedanib each are likely to have limited CNS penetration, as they are substrates of P-gp and/or Bcrp, whereas data are not available for tivozanib or dovitinib.37−39 Furthermore, for sorafenib, another study suggests that patients treated with renal cell carcinoma treated with sorafenib progress due to metastases only observed in the CNS, suggesting a sanctuary from drug due to lack of BBB penetration.40 Regorafenib (8, Table 2) demonstrated an effect in a rat model of glioblastoma41 and, accordingly, advanced to clinical studies for the treatment of GBM.42 While results are not available, efflux transport may limit free concentrations of regorafenib behind the BBB as the molecule is a substrate of P-gp and Bcrp and in P-gp/Bcrp knockout mice a 5.5-fold increase in brain concentration was achieved when compared to wild type mice at the same time point.43 The PDGFR-β, c-KIT, and Flt3 inhibitor tandutinib (9, Table 2) was found to be a substrate of both P-gp and Bcrp, which limits brain exposure in mice.44 Still, tandutinib was advanced to a phase I clinical trial in patients with GBM. In that study, brain concentrations in 6 patients were determined, and a mean brain-to-plasma ratio (total) in these patients was determined to be 0.33. However, no free brain-to-free plasma ratios or free brain concentration data from subsequent studies have been reported, and so no conclusion can be made about whether or not sufficient target engagment was achieved.45 After demonstrating in vivo efficacy in three different orthotopic GBM models in mice,46 axitinib (10, Table 2)47 encouragingly demonstrated activity in a phase II study of patients with GBM.48 However, it remains possible that the extent of benefit derived from axitinib treatment of GBM, where some tumor typically resides behind an intact BBB, may be limited due to the fact that axitinib is a significant substrate of P-gp and Bcrp. This was demonstrated in mouse pharmacokinetic studies in which P-gp/Bcrp knockout mice had

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VEGFR AND PDGFR Inhibition of angiogenesis has been established as a beneficial approach to treating cancer, and the potential of this approach to cancer treatment extends to cancers in the CNS.18 Targeting vascular endothelial growth factor receptors (VEGFRs) has been suggested to be of particular interest for the potential treatment of neurological tumors, as it is a known driver of angiogenesis in CNS tumors and found to be overexpressed in this setting, particularly the highly vascularized GBM.19 Additionally, platelet derived growth factor receptor (PDGFR), a kinase frequently inhibited by VEGFR inhibitors, has been identified as a potential target for the treatment of GBM due to 10033



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of our knowledge, there are no reports of preclinical in vivo studies describing free brain exposure or clinical study results evaluating brivanib for the treatment of CNS tumors. However, consistent with its lack of P-gp transport, cabozantinib has undergone a phase II study for the treatment of GBM and demonstrated some clinical and pharmacodynamic activity.62 Among the 15 VEGFR/PDGFR inhibitors discussed here and included in Table 2, just two have been reported to have minimal P-gp mediated efflux, of importance when targeting CNS malignancy. That two, cabozantinib and brivanib, are able to minimize P-gp transport demonstrates that it is possible to achieve with still potent kinase inhibitors and enables assessment of the validity of the hypothesis that inhibiting their targets might be an effective treatment approach for GBM.

14- and 21-fold increases in brain concentration at 1 and 4 h postdose when compared to wild type mice.49 Vandetanib (11, Table 2)50 and lenvatinib (12, Table 2)51 are additional VEGFR inhibitors that have advanced to clinical studies to treat GBM52,53 despite being reported substrates of P-gp.54,55 The ability to achieve efficacious free concentrations in the brain is a concern as P-gp efflux is anticipated to limit drug penetration to portions of tumor where the BBB remains intact. Whether or not vatalanib (13, Table 2)56 is a substrate of P-gp or Bcrp in vitro has not been reported, and there are not reports of brain penetration of this molecule either preclinically or clinically. Vatalanib was studied in phase I clinical trials in patients with glioma or GBM, but development of the molecule was halted prior to complete assessment in this patient population.57 Cabozantinib (14, Table 2)58 and brivanib (15, Table 2)59 stand out among the VEGFR inhibitors discussed here, as they are reported to not be substrates of P-gp transport, suggestive of their potential in the neurooncology setting.60,61 To the best

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EGFR The initial success of the epidermal growth factor receptor (EGFR) inhibitors erlotinib (16, Table 3)63 and gefitinib (17, Table 3)64 in the treatment of EGFR mutant non-small-cell

Table 3. Structures and Key Properties for EGFR Inhibitors Advanced to Clinical Studya

a

Properties for 119 marketed CNS drugs are included for comparison. *Median value of 119 marketed CNS drugs.12 10034



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lung cancer (NSCLC) was followed by the approval of afatinib (18, Table 3)65 and more recently osimertinib (19, Table 3).66 In addition to their use in the treatment of NSCLC, erlotinib and gefitinib have been evaluated for the treatment of NSCLC brain metastases that harbor activating mutations of EGFR. Despite some reported benefit of EGFR inhibitor treatment of EGFR mutant NSCLC brain metastases,67 it is also reported that such molecules are not as effective in the treatment of brain metastases as peripheral metastases, suggesting limited CNS penetration.68 In this scenario, the inhibitor may be able to effectively treat some, or a portion of, individual metastases where the BBB is compromised, yet lesions behind the BBB continue to grow. Consistent with this theory, PET imaging of 11 C-erlotinib showed accumulation of drug in a brain metastasis but not in normal brain tissue. These data suggest that where the BBB is intact, a “sanctuary” for tumor remains.69 That erlotinib was not capable of freely crossing the BBB was also established in a preclinical model of glioma.70 Gefitinib, afatinib, and osimertinib have each also been reported to be substrates of both P-gp and Bcrp, and so brain penetration of those EGFR inhibitors is expected to be limited.71−73 Nevertheless, what free concentration of afatinib that is capable of reaching CNS metastases in EGFR mutant-positive NSCLC has demonstrated benefit clinically.74 The interest in EGFR inhibitors for treating CNS cancer extends beyond brain metastases in NSCLC to GBM treatment. In the most common and aggressive form of brain cancer, GBM, overexpression of EGFR is encountered in approximately 40% of patients and half of these have an associated extracellular mutation of EGFR (variant III).75 These factors suggest the potential utility of a brain penetrant EGFR inhibitor. Several small molecule EGFR inhibitors, including gefitinib and erlotinib, have been approved for use in EGFR mutant NSCLC but, despite clinical study, have not resulted in approval for the treatment of gliomas.76 Investigation of brain penetrant inhibitors of EGFR would therefore be of interest. For rociletinib (20, Table 3)77 no associated P-gp efflux or brain penetration data have been reported. However, recently there have been two reports of EGFR inhibitors that, while maintaining the quinazoline core of earlier EGFR inhibitors, were reportedly designed to effectively penetrate the BBB to allow for effective treatment of CNS disease. The first, NT113 (21, Table 3), a pan-ERBB inhibitor, demonstrated efficacy in intracranial GBM xeongrafts, including those with high EGFR vIII expression.78 A limitation in the characterization of 21 is that, while brain-to-plasma ratios are reported, no free brain concentrations or free brain-to-free plasma ratios are reported, limiting the interpretation of just how effectively this molecule penetrates the BBB. Nevertheless, in intracranial GBM xenograft studies, 21 was more efficacious than either erlotinib or lapatinib, potentially indicating some improved degree of effective CNS penetration. A second recently disclosed quinazoline-based clinical EGFR inhibitor intended to cross the BBB is AZD3759 (22, Table 3).79 The disclosure of 22 describes the directed effort toward specifically identifying a brain penetrating inhibitor of EGFR for the treatment of CNS tumors, particularly CNS metastases that arise in the course of treatment of EGFR mutant NSCLC. In order to achieve the excellent brain penetration that 22 realizes compared to gefitinib (Figure 1), improving physical properties to reduce transporter mediated efflux was emphasized in the optimization effort. In this case, the number of rotatable bonds had an apparent correlation with

Figure 1. Structural modifications upon gefitinib (17), focused on reducing rotatable bonds and effective hydrogen bond donors, led to the freely BBB penetrating inhibitor of EGFR, 22.

efflux, and reduction of rotatable bonds, when compared to gefitinib, resulted in reduced transporter mediated efflux. Furthermore, the fluorine atom of gefitinib was moved to be positioned next to the NH of the aniline in 22 (Figure 1). This positioning allows for intramolecular interaction of the F atom with the NH, thereby “masking” the HBD, commonly associated with increased transporter mediated efflux. The structural modifications relative to gefitinib did not have an apparent detrimental impact on potency, as 22 and gefitinib are reported to have the same potency in a cellular assay employing an L858R EGFR mutant cell line, suggesting its potential in the treatment of NSCLC with EGFR mutant positive brain metastases. The team at AstraZeneca demonstrated the effective penetration of 22 across the BBB in preclinical species by reporting both Kpuu,brain and Kpuu,CSF values that show that the molecule achieves equivalent free concentrations on each side of the barrier in rats. The scientists at AstraZeneca went on to show extensive penetration of 22 into monkey brain in PET imaging studies. 22 also demonstrated remarkable efficacy in an in vivo model of brain metastasis. In this model, 22 clearly differentiates itself from erlotinib, which was not efficacious when administered at the same dose level as 22. While EGFR has been a long-standing target in GBM, previous molecules have not allowed for clinical conclusion on the validity of the target as transporter mediated efflux does not allow them to freely penetrate the BBB to where tumors reside. The recent emergence of 21 and, particularly, 22 highlights an exciting opportunity to study inhibition of a known driver of a significant percentage of GBM cases and NSCLC brain metastases. 21 and 22 are also part of a very limited set of kinase inhibitors reportedly specifically designed for the treatment of brain cancer.

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PI3K/AKT/mTOR In addition to targeting EGFR directly, another approach to treat GBM would be to target downstream kinases. The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) kinases comprise one such pathway and are implicated in a significant percentage of GBM and neuroblastoma cases.80−83 Targeting the PI3K/AKT/mTOR pathway is also suggested as a mechanism to treat human epidermal growth factor receptor 2 (HER2)-positive brain metastases.84 As a result of this biological implication and the pursuit of inhibitors of this pathway for other tumors, a number of agents have advanced to clinical trials in GBM patients.85 As the inhibitors of the PI3K/AKT/mTOR pathway have been reviewed in this context previously,85 we provide here a brief summary organized according to primary target of the inhibitor. Of the many PI3K/mTOR inhibitors that have entered clinical study, GDC-0084 (25),86 buparlisib (26),87 PX-866 (28),88 10035



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Table 4. Structures and Key Properties for PI3K Inhibitors Advanced to Clinical Study for Brain Cancer or FDA Approveda

a


Figure 2. Modifications of PI3K/mTOR inhibitors that resulted in the discovery of 25, a brain penetrating inhibitor with desirable metabolic stability.

pilaralisib (29),89 and XL765 (30)90 have been part of trials specifically for GBM (Table 4).83 Buparlisib has also advanced to clinical studies for the treatment of breast cancer patients with brain metastases.91 However, among these, only 25 was apparently designed to ensure significant free brain penetration. In order to realize 25, a program was initiated to purposefully identify a PI3K/mTOR inhibitor capable of crossing the BBB so that it would be amenable to treating GBM. These studies began with GNE-493 (23)92 as a starting point which was a potent inhibitor of PI3K and mTOR but was a substrate of P-gp and Bcrp (Figure 2).86 In order to realize brain penetrant analogs, the importance of reducing the number of hydrogen

bond donors in 23 was identified as critical. To further predict the likelihood of P-gp and Bcrp mediated efflux, as well as metabolic stability, in silico evaluations were used to prospectively evaluate designs. From these efforts GNE-317 (24, Figure 2) was first identified which demonstrated that a brain penentrant PI3K inhibitor differentiated from a PI3K inhibitor that does not penetrate the BBB (2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno[3,2-d]pyrimidine (GDC-0941),93 not shown) in that it had a PD effect in normal brain tissue and had improved efficacy in in vivo brain tumor models.94 24 was found to have unacceptable projected human clearance and so was further optimized to 25 (Figure 2), a molecule 10036



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The inhibitors 28, pilaralisib (29), and 30 have each progressed to clinical trials for the treatment of GBM, but there has not been a report of whether brain penetration was a design consideration or if these molecules penetrate the BBB. The PI3K and PI3K/mTOR inhibitors discussed above inhibit each of the class I PI3K isoforms (α, β, δ, and γ). However, the only as yet approved PI3K inhibitor is idelalisib (31), a selective inhibitor of the δ isoform of PI3K.99 Idelalisib is approved for the treatment of chronic lymphocytic leukemia. We were unable to identify any indications that CNS tumor progression is a mechanism of resistance to idelalisib. This is a potential risk, as idelalisib is reported to not penetrate the BBB,100 consistent with the disclosure that it is a substrate of both P-gp and Bcrp.101 Among mTOR inhibitors, the mTORC1 inhibitors everolimus (32), temsirolimus (33), and sirolimus (34) are FDA approved agents (Table 5).102 Each of these molecules has been studied in patients with GBM but has not provided benefit.83 Perhaps insufficient brain penetration is a contributing factor to

that is of comparable potency and has similar ability to cross the BBB to 24 but was projected to have more desirable human pharmacokinetic properties. The ability of 25 to potently inhibit PI3K/mTOR signaling in the brain, along with its desirable projected human pharmacokinetic profile, led to its advancement to clinical trials for the treatment of GBM. The report of the discovery of buparlisib (26) does not indicate that achieving brain penetration was a design consideration.87 However, in subsequent reports buparlisib has been reported to effectively cross the BBB and inhibit PI3K pathway signaling in preclinical95 and early clinical studies in patients with recurrent GBM.96 Unfortunately and despite inhibition of PI3K signaling in patient tumors, there was not substantial efficacy. Additionally, buparlisib has been reported to cause mood changes, a side effect not observed with other PI3K inhibitors in the clinical setting.84 The structurally related dual PI3K/mTOR inhibitor PQR309 (27) is reported to not be a substrate of P-gp97 and achieves equivalent brain and plasma concentrations,98 although free concentrations were not reported.

Table 5. Structures and Key Properties for mTOR Inhibitors Advanced to Clinical Study for Brain Cancera

a




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free brain concentrations, suggesting opportunity remains for AKT inhibitors that might be used to treat brain cancers.

the lack of efficacy, as everolimus and sirolimus are reported to be substrates of P-gp (and temsirolimus is a prodrug of sirolimus).103 AZD2014 (35)104 and CC-223 (36)105 are mTORC1/2 inhibitors that have advanced to GBM clinical trials.106,107 For 35, there is no indication of whether the molecule penetrates the BBB.108 In a clinical study of 36, GBM tumor-to-plasma ratios ranged from 16% to 77%.107 However, it is not possible to ascertain if sufficient concentrations to expect efficacy are achieved as free concentrations were not reported, including where the BBB is intact. Most encouraging of the clinical mTOR inhibitors from the perspective of trying to treat brain cancer, palomid 529 (37) has been reported to effectively cross the BBB as brain concentrations were similar in pharmacokinetic experiments comparing wild type mice and P-gp knockout mice.109 This makes 37 one of a small set of clinical kinase inhibitors (the only apparent mTOR inhibitor) where limited brain penetration would not be a principal factor in limiting conclusion on the value of a target. In addition to the inhibition of PI3K and mTOR, inhibition of AKT has received significant attention in this pathway.110 Among the clinical AKT inhibitors perifosine (38),111 8-(4-(1aminocyclobutyl)phenyl)-9-phenyl[1,2,4]triazolo[3,4-f ][1,6]naphthyridin-3(2H)-one (MK-2206, 125),112 PBI-05204 (39),113 4-(2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-{[(3S)-3piperidinylmethyl]oxy}-1H-imidazo[4,5-c]pyridin-4-yl)-2-methyl3-butyn-2-ol (GSK690693),114 uprosertib,115 XL-418 (structure not disclosed), (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin1-yl)-3-(isopropylamino)propan-1-one (GDC-0068),116 and 3-(3-(4-(1-aminocyclobutyl)phenyl)-5-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine (ARQ-092),117 we were only able to identify some indication of the likelihood of brain penetration, or advancement to a clinical study for use in brain cancer, for perifosine and 39 (Table 6). Ultimately, the allosteric AKT inhibitor perifosine was part of a trial in GBM patients but did not demonstrate efficacy,83 consistent with limited (total) brain penetration preclinically.118 In a preclinical study of 39, significant total brain concentrations were achieved in rats but no assessment of free concentration was determined.119 Additionally, for 125, a trial of GBM patients was deemed not suitable due to “questions regarding the ability of the drug to pass through the blood−brain barrier”.83 Achieving brain penetration was not an apparent design consideration for any clinical AKT inhibitor, and no clinical AKT inhibitor is conclusively capable of achieving signficant

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FGFR Fibroblast growth factor receptor (FGFR) kinase has been suggested as a potential target for the treatment of brain cancer,120,121 and numerous FGFR inhibitors have entered clinical development.122 As many of the FGFR inhibitors are nonselective, with many inhibiting VEGFR and PDGFR (discussed above), the focus of this section is limited to selective FGFR inhibitors that have entered clinical development (Table 7).123 Those inhibitors include AZD4547 (40),124 infigratinib (41),125 erdafitinib (42),126 CH5183284 (43),127 and ARQ 087 (structure not available). Of these, infigratinib has advanced to clinical studies in patients with GBM.128 However, we were unable to identify any data that suggest infigratinib is capable of penetrating the BBB. Similarly, we were unable to identify data informing the potential of erdafitinib, 40, or 43 to freely cross the BBB. On the other hand and of interest for its potential for the treatment of brain cancer, ARQ 087 was reported to achieve free brain-to-free plasma concentration ratios of about 0.1 in rats.129

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IGF-1R Type I insulin growth factor receptor (IGF-1R) has been identified as a potential target for the treatment of brain cancers,120,130 and numerous IGF-1R inhibitors have advanced to clinical trials.131 Among the clinical IGF-1R inhibitors (Table 8) linsitinib (44),132 BMS-754807 (45),133 BVP-51004 (46),134 XL-228 (47),135 and INSM-18 (48),136 there is no indication that achieving CNS penetration was a design consideration. 45 was demonstrated to have limited total brain penetration in mouse studies,137 and 48 is believed to be a substrate of P-gp.138 We were unable to identify data related to efflux transport or brain penetration of the other IGF-1R inhibitors. Unfortunately, the available data suggest that no clinical IGF-1R inhibitors are suitable to evaluate whether inhibition of this target would be beneficial for brain cancer treatment.

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CDKs In addition to aberrant EGFR and PI3K signaling pathways, activation of cyclin-dependent kinases (CDK) 4 and 6 is observed in a majority of GBM cases.82,139 Furthermore, CDK4/6 amplification is frequently observed in diffuse intrinsic pontine gliomas, a cancer of the brainstem.140 Among CDK4/6 inhibitors,

Table 6. Structures and Key Properties for Select AKT Inhibitors Advanced to Clinical Studya

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Table 7. Structures and Key Properties for FGFR Inhibitors Advanced to Clinical Studya

a

compd

primary kinase target

HBD

TPSA (A2)

cLogP

MW

40 41 42 43 CNS drugs*

FGFR FGFR FGFR FGFR N/A

3 2 1 4 1

91 95 77 105 45

4.4 4.7 4.3 3.4 2.8

464 560 447 356 305

preclinical assessment of brain penetration no no no no

data data data data

reported reported reported reported


Table 8. Structures and Key Properties for IGF-1R Inhibitors Advanced to Clinical Studya

a


palbociclib (49, Table 9)141 is approved for the treatment of hormone-receptor positive breast cancer. Regarding its potential for the treatment of brain cancer, palbociclib was demonstrated to provide a survival benefit in a genetic mouse model of brainstem glioma.142 Preclinical studies in three intracranial mouse models of GBM showed that palbociclib was efficacious either as a single agent or in combination with radiation.143 However, palbociclib was found at 25-fold higher concentration in tumor than in normal brain tissue, suggesting that the molecule has limited penetration into the brain and the BBB is compromised at the core of the tumor but not in normal brain tissue. Therefore, despite the reports of efficacy in brain cancer models, palbociclib may have free brain concentrations

below what is needed for efficacy in tumors where the BBB is intact. This would be consistent with being a substrate of P-gp,144 and ultimately an assessment of free brain concentrations or Kpuu,brain is necessary to draw a conclusion about the merits of palbociclib for use in brain cancer. Like palbociclib, abemaciclib (50)145 is reported to be a substrate of both P-gp and Bcrp.146 However, in mice and rats, Kpuu,brain is measurable at at least 0.2 and, while perhaps a model of modest utility, abemaciclib demonstrated efficacy in an orthotopic U87 GBM model in rats.146,147 While there is potential to further increase free brain penetration, given that some free brain exposure is attained with abemaciclib, it is encouraging that a trial studying abemaciciblib in breast cancer, 10039



Perspective

Table 9. Structures and Key Properties for CDK4/6 Inhibitors Advanced to Clinical Studya

a


Table 10. Structures and Key Properties for CDK1/2 Inhibitors Advanced to Clinical Studya

a


Flavopiridol (52, Table 10)151 has been shown to inhibit GBM tumor models in mice, including in the intracranial setting.152 However, the value of the in vivo efficacy may be limited by a compromised BBB, as flavopiridol is a substrate of both P-gp and Bcrp and significantly increased brain exposure is observed in P-gp/Bcrp knockout mice than in wild type mice.153 Seliciclib (53, Table 10) was reported to achieve a brain-toplasma ratio (AUC) of 0.3 after a 25 mg/kg oral dose to rats.154

non-small-cell lung cancer, or melanoma patients with brain metastases is currently enrolling.148 To the best of our knowledge, there is no evidence of brain penetration for other CDK4/6 inhibitors, including the clinical inhibitor ribociclib (51).149 In addition to the potential of CDK4/6 inhibition in the treatment of brain cancer, inhibition of CDK1 and CDK2 has been suggested as having potential application in the treatment of GBM.150 The CDK inhibitors that have advanced to the clinic that inhibit CDK1/2 tend to be broad spectrum CDK inhibitors (Table 10).149 10040



Perspective

to the brain. As a result, there are emerging best-in-class opportunities for kinase inhibitors that prevent resistance in that manner. An example of this phenomenon is seen in the case of anaplastic lymphoma kinase (ALK) fusion positive NSCLC.164 Crizotinib (59)165 was the first ALK inhibitor to show remarkable benefit to ALK-positive NSCLC patients.166 Unfortunately, disease progression on crizotinib therapy is inevitable. In fact, in the phase I and II trials of crizotinib in ALK-positive NSCLC, the most common mechanism of progression on therapy has been reported to be through CNS metastases.167,166 Crizotinib has poor free brain penetration, consistent with significant P-gp mediated efflux in vitro, which likely allows for metastases to find “sanctuary” in the CNS allowing for disease progression.168,169 As a result of relapse through CNS metastases, as well as resistance mechanisms including kinase domain mutations, there has been a substantial effort in identifying next-generation ALK inhibitors, which have been reviewed elsewhere.170 Among the many next-generation inhibitors (Table 11), several have been reported to be potentially effective in controlling CNS disease in ALK-positive NSCLC. In a small set of patients in a phase I trial, ceritinib (60)171 was reported to achieve responses in patients with brain metastases, including patients who had progressed on crizotinib.172 For ceritinib,

However, this only considers the total concentrations, and the free concentration ratio is likely to be lower as seliciclib is a reported substrate of P-gp.155 Dinaciclib (54, Table 10)156 has demonstrated potential utility in in vitro studies to treat GBM;157 however, we were unable to identify any data suggesting whether or not this molecule is likely to penetrate the BBB. Despite inhibition of neuroblastoma tumor cell growth in the in vitro setting,158 SNS-032 (55, Table 10) is a substrate of P-gp and brain penetration is limited in wild type mice compared to P-gp knockout mice.159 AT7519 (56, Table 10)160 appears to be a substrate of P-gp as it has less of an effect on P-gp overexpressing cell lines.161 We were not able to determine if R547 (57)162 and AZD5438 (58)163 are capable of crossing the BBB or are substrates of efflux transporters. Furthermore, we were unable to identify any indication that achieving CNS penetration was a design consideration in the discovery of any of the inhibitors of the CDKs 1 and 2. Taken together, there remains an apparent lack of a CNS penetrating CDK1/2 inhibitor if clinical assessment of this target for the treatment of GBM is to be assessed.

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ALK Outside primary brain tumors, there is a growing recognition of the ability of peripheral tumors to escape therapy via metastasis

Table 11. Structures and Key Properties for ALK Inhibitors Advanced to Clinical Studya

a




Perspective

Figure 3. Macrocyclization led to improved metabolic stability, potency, and reduced P-gp mediated efflux in this series of ALK inhibitors.

activity against both EML4-ALK fusion proteins and crizotinib resistant ALK mutants, was designed to be a brain penetrant ALK inhibitor by reducing P-gp transport.169 As resistance to crizotinib is acquired through various kinase mutations as well as CNS metastases, the Pfizer program sought to achieve a molecule that would simultaneously overcome both of those resistance mechanisms.169 Initial analogs capable of potently inhibiting crizotinib resistant ALK mutations did not achieve a desirable balance of potency with physicochemical properties that allowed for both good metabolic stability and low P-gp mediated efflux. Crystallographic information was utilized to design subsequent ALK inhibitors with improved lipophilic efficiency. The “U-shape” that ligands adopted in a cocrystal structure with ALK inspired macrocyclic analogs. A 12-membered ring lactam was found to improve human liver microsomal stability and reduce P-gp efflux when compared to its acyclic counterpart (66 vs 67, Figure 3). Rather than focusing on the influence of single physicochemical properties on P-gp mediated efflux, the Pfizer group emphasizes the need for multiparameter optimization due to an interplay of the influence of numerous physicochemical properties on efflux. In particular, HBD, log D, and MW were each considered in parallel. In these studies, acyclic analogs had higher levels of P-gp mediated efflux than the macrocycles with comparable MW, log D, and HBD. 66, like the other macrocycles as well as acyclic analogs described, takes advantage of an intramolecular hydrogen bond between the aminopyridine and the adjacent ether oxygen. This intramolecular hydrogen bond may effectively mask a HBD. The authors also suggest that the macrocycles may have reduced efflux relative to acyclic analogs due to a reduced number of rotatable bonds and a 10% smaller solvent-accessible surface area.169 Ultimately, 66 achieves a free brain-to-free plasma AUC ratio of 0.2 after oral administration in rats. In summary, ALK is one of a few kinase targets, along with PI3K, EGFR, and PLK (below), where discovery programs have been reportedly directed specifically at achieving brain penetrating inhibitors. With such an ALK inhibitor undergoing clinical study currently, evaluation of the clinical hypothesis can take place.

medicinal chemistry optimization did not apparently focus on achieving free brain exposure.171 While, to the best of our knowledge, P-gp transport or free brain penetration was not apparently a factor in the design of the molecule, alectinib (61)173 is reported to be efficacious in preclinical models of brain metastases and, aiding in the positive interpretation of the efficacy results, alectinib is reportedly not a substrate of P-gp.174 Most significantly, alectinib has been reported to achieve responses in patients with CNS disease that did not respond to crizotinib, indicating some degree of brain penetration.175 Entrectinib (62)176 is reportedly capable of crossing the BBB in preclinical species, although free brain concentrations were not reported. Encouragingly, a clinical report of a NSCLC patient with brain metastases who had a response to entrectinib suggests that the molecule may achieve significant free CNS penetration.177 ASP3026 (63)178 was reported to achieve a brain-to-plasma ratio (AUC0−24h) of 0.72 in mice.179 Free brain-to-plasma ratios were not reported, however. Brigatinib (64)180 is another nextgeneration ALK inhibitor that has some preliminary indication of efficacy in a cohort of 10 crizotinib resistant patients with brain metastases.181 Brigatinib was able to achieve a response in a mouse intracranial tumor model, and 11C brigatinib was visualized within the tumor. However, in these studies, the extent to which the BBB was compromised was not reported and higher concentrations of brigatinib were observed in the intracranial tumor than in normal brain tissue.181 While insufficient preclinical data exist to understand the extent to which free brigatinib is capable of penetrating the BBB, very encouraging clinical data are emerging showing that brigatinib is effective in treating ALK-positive brain metastases, where crizotinib was ineffective, suggesting meaningful CNS penetration of brigatinib in these patients.182 X-376 (65)183 and X-396 (structure not disclosed, 126) are additional ALK inhibitors. 126 is reported to have a brainto-plasma ratio in mice comparable to that of crizotinib (a P-gp substrate with low CNS exposure in humans). However, the investigators suggest that due to the greater potency of 126, there may be potential for efficacy in the CNS setting.183 No reports of free brain levels are reported, however. While each of the aforementioned next-generation ALK inhibitors (Table 10) may hold potential for treating ALKpositive malignancy, there is insufficient preclinical data to demonstrate that these molecules lack transporter mediated efflux and/or achieve significant free brain exposure. PF-06463922 (66, Table 11)169 clearly stands out among the next generation ALK inhibitors, as achieving free brain penetration was an evident design consideration. 66, which has

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HER2 A parallel to the resistance to initial ALK inhibitors via brain metastasis is observed in the treatment of HER2-positive breast cancer with antibody therapeutics. Among patients treated with trastuzamab (Herceptin), CNS metastases emerge in approximately 30% of patients.184 Lapatinib (68, Table 12) is approved as a small molecule HER2/EGFR inhibitor,185 but preclinical studies showed that therapeutic concentrations were not achieved 10042



Perspective

Table 12. Structures and Key Properties for HER2 Inhibitors Advanced to Clinical Studya

a


in brain metastases,186 suggesting that lapatinib does not effectively cross the BBB and would not be expected to be efficacious in that setting. Furthermore, a study of brainto-plasma concentration ratios in mice shows that lapatinib is a

substrate of P-gp and Bcrp.187 Indeed, in the clinical setting lapatinib was found to have variable and limited penetration into HER2-positive brain metastases.188,91 Aside from lapatinib, at least a dozen additional small molecule inhibitors 10043



Perspective

The data available for tucatinib and 71 demonstrate that brain penetrant inhibitors of HER2, which would be of evident interest in the treatment of HER2-positive brain metastases, are achievable, and it is encouraging that a potential treatment for HER2-positive brain metastases may be realized.

of HER2 have been reported to have advanced to clinical study (Table 12).189 Among the HER2 inhibitors that have advanced to clinical studies, neratinib (69),190 a pan-HER inhibitor, and tucatinib (70)191 have advanced to trials for breast cancer patients with brain metastases. Unfortunately, a phase II trial of neratinib in patients with HER2-positive brain metastases was not successful. The lack of efficacy attained in the trial may be due in part to the noted lack of CNS penetration of neratinib, determined in preclinical studies192 and consistent with a report that it is a P-gp substrate.193 For tucatinib, on the other hand, an active metabolite is reported to achieve brain-to-plasma concentration ratios ranging from 0.5 to 2.1 across several time points after a 75 mg/kg oral dose in mice.194 While only total concentration ratios were reported, and so a true indication of free brain penetration is not available, in other studies tucatinib was capable of inhibiting p-HER2 in mouse brain tissue, demonstrating some extent of free exposure. Additionally, tucatinib achieved a survival benefit in mice in an intracranial HER2-positive xenograft study.191 TAK-285 (71)195 is a clinical inhibitor of HER2 and EGFR that has been demonstrated to be capable of penetrating the BBB in preclinical studies. In rats, the free brain-to-free plasma (AUC) ratio was 0.24 after a 75 mg/kg oral dose.196 Additionally, 71 was demonstrated to not be a substrate of P-gp and to confer efficacy in a mouse model of HER2-positive brain metastases.197 Taken together, the data are supportive of evaluating 71 in the clinical treatment of patients HER2positive brain metastases. Dacomitinib (72)198 inhibits epidermal growth factor receptors and other tyrosine kinases. A clinical study is looking at the safety and effectiveness of using dacomitinib to treat HER2-positive breast cancer patients with progressive brain metastases (NCT02047747). Unfortunately, there are apparently no data available on whether dacomitinib is a substrate of efflux transporters that are expressed at the BBB. The pan-HER inhibitor AC480 (73)199 was utilized in a study of patients with GBM in which the tumor was surgically resected after drug administration. This study showed that 73 had concentrations in the tumor and brain that were greater than in plasma, although no indication of free concentrations has been reported that would help to interpret whether efficacy could have been expected.200 The HER2/EGFR/VEGFR inhibitor AEE788 (74)201 was of interest for the treatment of brain cancers. In preclinical studies, 74 had activity against medulloblastoma cell lines and a xenograft (flank).202 While 74 was reported to confer a survival benefit in an orthotopic model of glioblastoma in mice, we were not able to identify reports of whether 74 is an efflux transporter substrate or if it is capable of free brain penetration.203 Unfortunately, a phase I trial of 74 enrolling GBM patients needed to be discontinued due to toxicity of the molecule without benefit.204 Pelitinib (75)205 is another HER2/EGFR inhibitor that has advanced to clinical studies but is reported to be a substrate of Bcrp which might limit its CNS exposure.206 The HER2 inhibitor CP-724,714 (76)207 was reported to be a substrate of both P-gp and Bcrp and, accordingly, would not be expected to be able to effectively cross the BBB.208 CUDC-101 (77),209 sapitinib (78),210 and AST1306 (79)211 have advanced to clinical trials, but we were unable to identify whether or not these molecules are substrates of efflux transporters or whether they are capable of free penetration of the BBB.

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b-Raf/MEK Historically, melanoma patients have a high frequency (>90%) of brain metastasis development, and once present, these patients typically survive for less than 6 months.212 Recently, inhibitors of the V600E mutation of b-Raf (vemurafenib (80)213 and dabrafenib (81)214) and mitogen activated protein kinase (MEK) inhibitors (cobimetinib (85)215 and trametinib (86)216), along with the combination of dabrafenib and trametinib, have received approval for the treatment of melanoma. As b-Raf (including V600E mutant) and MEK inhibitors are used in the treatment of melanoma, it is important to consider how effectively these agents cross the BBB to either treat or prevent CNS metastases.217 Additionally, b-Raf218 and MEK219 have been identified as potential targets for primary brain tumors. At least seven Raf inhibitors220 and more than a dozen MEK inhibitors221 have entered clinical studies. Among the clinical Raf inhibitors (Table 13), there have been conflicting reports of clinical response of CNS metastases to vemurafenib (80)222 or dabrafenib (81)223 therapy, ranging from ineffective at treating brain metastases to a case of a complete response. Both vemurafenib and dabrafenib have been reported to be substrates of P-gp and Brcp and, furthermore, achieve little free brain penetration in mouse studies.224,225 The varied reports and modest clinical response rates could be attributed to inconsistent disruption of the BBB, and potentially greater rates of response could be achieved if a b-Raf inhibitor were capable of free brain penetration. Raf-265 (82)226 does not apparently effectively cross the BBB, as that molecule conferred efficacy in a mouse tumor model when implanted in a flank but not when implanted intracranially.227 We were unable to identify any information suggesting whether or not the clinical Raf inhibitors encorafenib (83),228 XL281 (structure not disclosed), RO5212054 (structure not disclosed), ARQ-736 (84),229 or its active metabolite, are capable of penetrating the BBB or are efflux transporter substrates. Together, the available data suggest that a BBB penetrating Raf inhibitor remains elusive, yet there would be significant potential value for such an inhibitor in treating cancers that metastasize to the brain. The approved MEK inhibitors cobimetinib (85, Table 14) and trametinib (86, Table 14) have each also been reported to have limited free brain penetration in mice due to P-gp and Bcrp mediated efflux.230,224 Additionally, neither cobimetinib nor trametinib inhibited pERK in normal brain tissue in mice after oral administration despite inhibition in the periphery, further illustrating a lack of CNS penetration by these molecules.231 Furthermore, when coadministered, dabrafenib and trametinib had low mouse brain exposure as well.224 Among the other clinical MEK inhibitors,221 we were unable to identify any data that would suggest that GDC-0623 (87), binimetinib (88), selumetinib (89), CI-1040 (90), TAK-733 (91), RO5126766 (92), or WX-554 (structure not disclosed) would be likely to penetrate the BBB. Nevertheless, selumatinib and binimetinib have been studied clinically for the treatment of brain cancers.232,233 The MEK inhibitor PD0325901 (93)221 inhibited tumor growth in a LN229 intracranial glioblastoma mouse xenograft 10044



Perspective

Table 13. Structures and Key Properties for b-Raf Inhibitors Advanced to Clinical Studya

a


tumor model study.219 Additionally, that 93 is capable of penetrating the BBB in rats was demonstrated by significant inhibition of pERK in normal brain tissue after oral administration of the drug. This molecule was found to have neurologic toxicities clinically, and with the hope to avoid similar toxicities, refametinib (94) and RO4987655 (95) were reportedly designed specifically to not penetrate the BBB.234,235 Accordingly, despite substantial peripheral exposure in rat or mouse studies, inhibition of pERK in brain tissue by those molecules was negligible. Likewise, AZD8330 (96)221 is reported to achieve minimal CNS penetration in rats.236 Pimasertib (97)221 has been reported to inhibit pERK in mouse brain tissue, indicating some degree of CNS penetration.237 Consistent with those results, pimasertib was reported to not be a substrate of efflux transporters.238 E6201 (98),239 an inhibitor of MEK and other kinases, has been shown to achieve total brain-to-plasma concentration ratios of 4.8−6.4 in rodents, although free concentrations were not reported. To support the suggestion that some 98 is free to engage its target in mouse brains, the molecule demonstrated a survival benefit in a mouse model of brain metastases.240 While in no case was achieving free brain penetration of a MEK inhibitor a reported design consideration, two clinical MEK inhibitors discussed above have achieved significant CNS concentration in preclinical studies. Worth noting, those two MEK inhibitors (93 and 97) each have a dihydroxy hydroxamate moiety (the only two among those in Table 14) and have four nominal hydrogen bond donors. It is therefore curious that the physical properties of 93 and 97 are so inconsistent with the median values of marketed CNS drugs in the HBD category, which is known to have a substantial impact

on P-gp efflux. However, both 93 and 97 have the potential for multiple intramolecular hydogen bonding interactions which could reduce both the effective HBD count and polarity of these molecules. While the brain penetrant MEK inhibitors offer opportunity to study their benefit in patients with brain cancer, 93 also highlights the additional risk that brain penetration of small molecule drugs adds to to an already difficult development path. Both on- and off-target activities in the brain have the potential to render a drug less tolerated, potentially limiting the ability of such a molecule to benefit patients with peripheral malignancy.

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PLK1/AURORA KINASES Both Polo-like kinase (PLK)241 and Aurora kinases have been suggested as targets for the treatment of brain cancers.242,243 Among the PLK1 inhibitors that have advanced to the clinic (Table 15), volasertib (99),244 BI 2536 (100),245 GSK 461364 (101),246 rigosertib (102),247 and NMS-P937 (103)248 have been shown to be substrates of P-gp, and therefore, CNS penetration is expected to be limited. The PLK1 inhibitor TAK-960 (104, Table 15), however, was reportedly selected among other analogs because it had reduced P-gp mediated efflux, suggesting the potential for CNS penetration.249 In the discovery of 104, it was noted that incorporation of a substituent capable of acting as a hydrogen bond acceptor adjacent to an amide, effectively eliminating a hydrodgen bond donor via intramolecular hydrogen bond, was essential to reduce P-gp mediated efflux (Figure 4). At least 15 Aurora kinase inhibitors have advanced to clinical studies.250 We were unable to identify considerations of achieving 10045



Perspective

Table 14. Structures and Key Properties for MEK Inhibitors Advanced to Clinical Studya

a


midostaurin (109), and UCN-01 (110).253 Among these, enzastaurin was part of a trial for the treatment of GBM,254 as well as for the treatment of brain metastases from lung cancer,255 but in each case it did not demonstrate significant benefit. Along with enzastaurin, we were unable to identify any data suggesting whether or not bryostatin or midostaurin is capable of penetrating the BBB or is a substrate of efflux transporters P-gp or Bcrp. The PKC inhibitor 110 achieved total brain-to-plasma concentration ratios of 0.5−1.0 at five different time points after a 3.5 mg/kg dose to rats.256 However, free concentrations are not reported, and so a proper interpretation of free brain penetration is not available from this study. Additionally, 110 is a reported substrate of P-gp, anticipated to limit CNS penetration.257

CNS exposure in the discovery of those molecules. Among those Aurora kinase inhibitors that have entered clinical studies, any discussion of potential BBB penetration is limited to tozasertib (105)250 and alisertib (106)250 (Table 16) which were each reported to inhibit tumor growth in orthotopic GBM models in mice, which is insufficient to understand the extent to which those molecules are capable of freely penetrating the BBB.243,251

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PKC Protein kinase C (PKC) has been identified as a potential target for the treatment of GBM.252 Among the small molecule PKC inhibitors that have entered clinical studies for the treatment of cancer (Table 17) are bryostatin (107), enzastaurin (108), 10046



Perspective

Table 15. Structures and Key Properties for PLK Inhibitors Advanced to Clinical Studya

a


Table 16. Structures and Key Properties for Clinical Aurora Inhibitors for Which BBB Penetration Data Are Availablea

Figure 4. Reducing effective HBD count by intramolecular hydrogen bonding reduced P-gp efflux among a set of PLK1 inhibitors.

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ABL AND Src The discovery of imatinib (111, Table 18)258 has rightfully been heralded as a remarkable success story in targeted therapeutics for the treatment of patients with Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML) or acute lymphoblastic leukemia (ALL). Despite initial responses, however, in addition to the emergence of resistance mutations,259 brain metastases lead to progression on imatinib therapy in nearly 20% of patients.260 Such CNS resistance likely emerges due to the poor ability of imatinib to cross the BBB, demonstrated both preclinically and clinically, as it is a P-gp and Bcrp substrate.261 Dasatinib (112, Table 18) was discovered as a next-generation Bcr-Abl inhibitor that potently inhibits imatinib resistant mutant forms of the enzyme.262 Dasatinib also inhibits Src, among other kinases,263 which has been identified as a potential target for the

compd 105 106 CNS drugs*

primary kinase target

HBD

TPSA (A2)

cLogP

MW

pan-Aurora Aurora A N/A

3 2 1

102 105 45

4.8 6.2 2.8

465 519 305

preclinical assessment of brain penetration insufficient data insufficient data

a


treatment of GBM as well as a target for patients with brain metastases.264 Like imatinib, dasatinib is a substrate of both P-gp and Bcrp which limits its brain penetration.265 Yet, despite approximately 10% (total) brain penetration (relative to plama) in an intracranial mouse model of Ph+ CML, dasatinib was able to demonstrate a therapeutic benefit. The authors attribute the efficacy to the exceptional potency of dasatinib against the 10047



Perspective

Table 17. Structures and Key Properties for PKC Inhibitors Advanced to Clinical Studya

a


Table 18. Structures and Key Properties for Abl or Src Inhibitors Advanced to Clinical Studya

a


relevant enzymes driving tumor growth.266 In a small clinical study, all of the 11 evaluable patients with CNS chronic myeloid leukemia responded to dasatinib therapy. Also, of 22 patients

from whom CSF samples were obtained, dasatinib was detectable in 6 of those patients, with CSF-to-plasma (total) of 0.05−0.28.266 These encouraging results suggest that a CNS 10048



Perspective

was significantly improved with coadministration of a P-gp inhibitor, implying bafetinib is a significant substrate of that transporter.278 While achieving CNS penetration is not discussed as a design consideration in the discovery of saracatinib (117),279 in preclinical studies it was reported to achieve brain-to-plasma concentration ratios of about 0.5 and CSF-to-plasma ratios of about 0.2.280 The brain and plasma concentrations reported were total (as opposed to free), and so there is a limit to the interpretation of brain penetration of this agent. However, in a clinical study evaluating saracatinib in Alzheimer’s patients, CSF-to-free plasma ratios were about 0.3, indicating some ability of this molecule to freely reach the CNS.281

penetrant Bcr-Abl inhibitor has potential for significant clinical benefit. Adding to data suggesting the benefit of CNS penetrant Bcr-Abl inhibitors, bosutinib (113) is another inhibitor of Bcr-Abl and Src family kinases, along with other kinases.263 In rats, bosutinib has been reported to achieve brain-to-plasma ratios ranging from 2.0 to 0.4; however there was not an accounting for free concentrations, so interpretation is limited. Yet bosutinib is reported to not be a significant substrate of P-gp or Bcrp.267 While there has been a report of a patient with ALL, which includes the CNS, who achieved a response to bosutinb,268 a phase II clinical trial of bosutinib in patients with GBM was halted early due to lack of benefit.269 Nilotinib (114) has been reported to be a substrate of P-gp,270 and achieving CNS penetration was not a reported consideration in its discovery.271 Despite this, in a small clinical study of four patients with CNS progression of CML, nilotinib was able to achieve a median CSF-to-plasma (total) ratio of 0.53%. With plasma protein binding reported to be 98% for nilotinib, this would translate to an approximately 26% CSF-to-free plasma ratio.272 Along with the apparent CNS penetration, 3 of the 4 patients had a clinical response to nilotinib.272 Further suggestive of some CNS penetration of both nilotinib and bosutinib are reports describing the use of these molecules in preclinical models of neurodegeneration in which pharmacodynamic modulation changes are observed in rodent brains.273 In the initial report describing the discovery of the Bcr-Abl inhibitor ponatinib (115), brain penetration was not reported as a design consideration.274 Still, the authors suggest that ponatinib is capable of crossing the BBB, as in a mouse study, a brain/plasma concentration ratio of 1.6 was achieved. As total (as opposed to free) concentrations were used to calculate the ratio, little conclusion can be drawn about how effectively ponatinib is capable of crossing the BBB based on that data. Suggesting that the action of P-gp and Bcrp actually does limit penetration of ponatinib across the BBB is a study comparing brain and plasma exposure in both wild type and P-gp/Bcrp knockout mice. In this study, the AUCbrain in the transporter knockout mice was 18-fold higher than in wild type mice.275 Bafetinib (116)276 is a Bcr-Abl/Lyn inhibitor that has advanced to clinical study for the treatment of brain cancers. Unfortunately, in a clinical study monitoring brain concentrations by microdialysis, bafetinib was demonstrated to not effectively cross the BBB.277 Consistent with the clinical findings, preclinical studies demonstrated that efficacy in a preclinical CNS cancer model

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c-Met Inhibition of c-Met has been suggested as a possible approach to treat brain cancer.282 The clinical c-Met inhibitor foretinib (118)283 has been reported to achieve brain-to-plasma ratios approaching 0.2 in mice; however, only total concentrations were reported.284 SGX523 (119),285 a c-Met inhibitor, was reported to confer efficacy in an orthotopic U87 xenograft model.286 However, no indication of the extent of brain penetration of the molecule or whether it is a substrate of efflux transporters is available, and so a conclusion on the expected potential utility of this molecule for the treatment of CNS malignancy cannot be drawn. Although numerous other nominal c-Met inhibitors have entered clinical trials,287 we were unable to identify any indication that these molecules288 achieve brain penetration (Table 19).

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FAK/Pyk2 Focal-adhesion kinase (FAK) and proline rich tyrosine kinase 2 (Pyk2) have been implicated as potential targets for the treatment of brain cancers.289 Additionally, four FAK or FAK/ Pyk2 inhibitors have advanced to clinical study (Table 20).290 For PF-562,271 (120),291 defactinib (121),292 and PND-1186 (122)293 we were unable to to identify any reported characteristics that would indicate whether the molecule is capable of penetrating the BBB. GSK-2256098 (123)294 is reported to have “poor” penetration of the BBB in rodent PK studies. By PET, in human GBM patients, significant brain and tumor concentrations relative to blood are reported but nonspecific binding was not apparently factored.295 Taken together, it appears that potential opportunity remains for the identification of a FAK and Pyk2 inhibitor that is capable of reaching brain tumors behind the BBB.

Table 19. Structures and Key Properties for Clinical c-Met Inhibitors for Which Discussion of Brain Penetration Was Found in the Literaturea

a

compd

primary kinase target(s)

HBD

TPSA (A2)

cLogP

MW

preclinical assessment of brain penetration

118 119 CNS drugs*

MET, RON, Axl, VEGFR MET N/A

2 0 1

111 73 45

4.2 2.6 2.8

633 359 305

insufficient data insufficient data




Perspective

Table 20. Structures and Key Properties for FAK/Pyk2 Inhibitors Advanced to Clinical Studya

a


Table 21. Structure and Key Properties for the BTK Inhibitor Ibrutiniba

a

Properties for 119 marketed CNS drugs are included for comparison. *Median value of 119 marketed CNS drugs12

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TGFβ-R Inhibition of transforming growth factor receptor β (TGFβ-R) kinase activity has been identified as a potential mechanism to treat glioblastoma.296 The TGF-β inhibitors galunisertib and TEW-7197 (structure not disclosed) have been reported to have advanced to clinical trials.297 However, considerations of brain penetration are not reported for these molecules.

In a small study, each of three patients with CNS involvement in MCL responded to ibrutinib (two with complete response of CNS lesions).303 Futhermore, in the two patients evaluated, concentrations in the CSF were significant and expected to be efficacious. The CSF-to-blood ratios ranged from 1% to 7%, but free plasma concentrations would likely indicate a greater free percentage of CNS penetration. Consistent with the free exposure in the CSF, ibrutinib is reported to not be a substrate of P-gp,304 an encouraging aspect of this molecule for the treatment, or prevention, of CNS progression of hematological malignancies for which it is used.

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PIM1 KINASE PIM1 kinase has been identified as a potential target for the treatment of GBM.298 The PIM inhibitors N-((1-methylpiperidin-4-yl)methyl)-3-(3-(trifluoromethoxy)phenyl)imidazo[1,2b]pyridazin-6-amine (SGI-1776),299 N-(4-((1R,3S,5S)-3-amino5-methylcyclohexyl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide (LGH447),300 and (R,Z)-5-((2-(3-aminopiperidin-1-yl)-[1,1′-biphenyl]-3-yl)methylene)thiazolidine-2,4-dione (AZD-1208)301 have advanced to clinical trials, but we were unable to identify data suggesting whether or not these molecules are substrates of efflux transport or are capable of freely penetrating the BBB.

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OTHER KINASES Numerous other kinases have been suggested to be of potential interest as targets for the treatment of brain cancer. Ataxia telangiectasia mutated (ATM),305 Mer, and Axl306 are among kinases that have been reported as potential targets for brain cancer but for which no discussion of brain penetration for clinical molecules exists or no molecule has advanced to clinical study for brain cancer treatment.

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CONCLUSION In the above sections, the availability of data suggesting whether or not kinase inhibitors of various targets have the potential for free CNS penetration and, therefore, potential in the treatment of brain tumors is discussed. Among the kinases examined here that have a biological rationale to be targeted with inhibitors

BTK Ibrutinib (124)302 (Table 21) is an inhibitor of Bruton’s tyrosine kinase (BTK) that has been approved for use in some hematological cancers including mantle cell lymphoma (MCL). While rare, CNS metastases can arise in patients with MCL. 10050



Perspective

for the treatment of brain cancers, a distinct minority have CNS penetrant inhibitors that have advanced to clinical study (Table 22). Furthermore, while CNS penetrant inhibitors are

Table 23. Comparison of Median Values of Physicochemical Properties for Kinase Inhibitors Discussed above That Are (a) Reported or Predicted (Based on Efflux Transport Data) To Have Limited CNS Penetration or (b) Reported To Have Significant Free CNS Penetration and/or No Significant P-gp or Bcrp Effluxa

Table 22. Kinases of Interest for Brain Cancer and Whether or Not CNS Penetrating Clinical Inhibitors Are Available kinase targets with CNS penetrant clinical inhibitors available

kinase targets without known CNS penetrant clinical inhibitors

EGFR Pl3K/mTOR CDK4/6 ALK HER2 MEK Abl/Src BTK

VEGFR AKT lGF-1R CDK1/2 b-RAF PLK1 Aurora PKC c-MET FAK/Pyk2 TGFR-β PlM1 ATM Mer AXL FGFR

kinase inhibitors median property value

limited CNS penetration (n = 48)b

CNS penetrating (n = 20)b

CNS drugs (n = 119)c

cLogP cLogD7.4 TPSA (Å2) HBD MW c_pKa

4.3 3.3 92 2 479 8.3

4.1 3.4 98 2 483 6.5

2.8 1.7 45 1 305 8.4

a

Median values of marketed CNS drugs are included for comparison. Kinase inhibitors CNS penetration categorization assigned based on data in discussions above. A complete list of the kinase inhibitors assigned to each category and their calculated physicochemical properties is provided in Supporting Information. cMarketed CNS drugs. Values obtained from ref 12.

b

Possibly affecting the quality of the data set and preventing emergence of additional differentiation in the properties between the groups, however, is a lack of free-brain-to-free-plasma drug concentration ratios for most molecules. That is, perhaps additional data and application of more stringent criteria to designate molecules as CNS penetrating might yield different results. Additionally, as discussed next, there are limitations to the use of calculated physical properties that might conceal actual differences between molecules. Also, while rare, there is a potential for species differences in P-gp to affect the interpretation of reported data. There are very few reports of the design of kinase inhibitors specifically for the treatment of brain cancer. We identified only five molecules, 21, 22, 25, 66, and 104, for which achieving brain penetration was a design intent. In the discovery of three of those five molecules (22, 66, and 104), intramolecular hydrogen bonds were utilized to effectively mask at least 1 HBD, which would not be accounted for in the calculated properties of those molecules. Furthermore, such intramolecular hydrogen bonds would also affect effective polar surface area. It is possible that other CNS penetrant kinase inhibitors also, whether intentionally or not, employ such a mechanism to avoid efflux transport to achieve their penetration (e.g., 93 and 97). Regardless, this is an approach that is worth consideration on kinase programs requiring CNS penetration. As drug discovery programs have increased their appreciation for what consitutes meaningful (free) brain penetration in recent years, the potential for this understanding to impact the discovery of new treatments of brain cancer is evident. Over the previous decades, a large number of kinase inhibitors advanced to clinical study for brain cancer treatment where, given the understanding of CNS penetration available today, negative outcomes were predictable given limited free access of the drug to its target. In fact, such studies should now be considered unjustified. Treating primary brain tumors with kinase inhibitors requires brain penetrant versions of those molecules and opportunity abounds for the pharmaceutical industry to treat these already significant unmet needs. Additionally, as kinase inhibitors are approved for the treatment of peripheral cancers, the emergence

available for some kinases, their evaluation has not yet concluded, so no conclusion on the validity of the hypotheses of inhibiting their targets to treat brain cancer can yet be drawn. It is important to note that only evidence of free CNS penetration or lack of P-gp/Bcrp transport of clinical inhibitors was considered in determining whether a kinase target has a tool to assess it as a target for treatment of CNS tumors (i.e., its categorization in Table 22). In reality, many other additional variables impact evaluation of a hypothesis clinically (e.g., PK, selectivity profile, safety, extent of free brain penetration, etc.), and so even for targets where CNS penetrant clinical inhibitors are available, lack of benefit may be encountered in the clinic for other reasons. Therefore, for each indicated kinase target discussed here, opportunity may remain for additional or improved inhibitors that are specifically designed to treat brain cancers, even where a brain penetrant inhibitor already exists and for which a known liability might be addressed. The paucity of CNS penetrant kinase inhibitors also limits study of combinations of brain penetrant kinase inhibitors, which may be a necessary treatment approach for certain tumors.307 Of the kinase inhibitors included in the above discussion, we identified 68 as having evidently limited CNS penetration (n = 48; molecules that achieve low free or total brain concentrations or are reported substrates of P-gp/Bcrp) or where some CNS penetration was evident/anticipated (n = 20; molecules that achieve meaningul free brain concentrations or are reportedly not substrates of P-gp/Bcrp).308 In Table 23 we compare the physicochemical properties of kinase inhibitors identified in the discussion above as CNS penetrating to those that have limited CNS penetration, as well as 119 marketed CNS drugs. There is remarkable similarity in the median values of cLogP, cLogD7.4, TPSA, HBD, and MW among the two categories of kinase inhibitors (mean values are also very similar). The only significant differentiation between the two classes of kinase inhibitors was in the calculated pKa category (which can affect HBD count for those sufficiently basic), where CNS penetrating kinase inhibitors have a lower median pKa than either kinase inhibitors that do not cross the BBB or CNS drugs. 10051



Perspective

protein kinase B; mTOR, mammalian target of rapamycin; HER2, human epidermal growth factor receptor 2; FGFR, fibroblast growth factor receptor; IGF-1R, type I insulin growth factor receptor; CDK, cyclin-dependent kinase; ALK, anaplastic lymphoma kinase; MEK, mitogen activated protein kinase; PLK, Polo-like kinase; PKC, protein kinase C; Ph+, Philadelphia chromosome positive; CML, chronic myeloid leukemia; ALL, acute lymphoblastic leukemia; FAK, focaladhesion kinase; Pyk2, proline rich tyrosine kinase 2; TGFβ-R, transforming growth factor receptor β; BTK, Bruton’s tyrosine kinase; MCL, mantle cell lymphoma; ATM, ataxia telangiectasia mutated

of brain metastases is expected when the treatments are not BBB penetrant (e.g., ALK, HER2, EGFR, etc.). Whereas in discovery programs brain penetration might be considered a liability for potential CNS safety reasons, limiting brain penetration might ultimately result in a resistance mechanism clinically via brain metastasis. In this scenario, best-in-class opportunities may emerge where brain penetrating kinase inhibitors can be realized. Whether for primary brain cancers or brain metastases, that so few kinase inhibitors have been reportedly designed to achieve CNS penetration suggests that the lack of advancement in the treatment of brain cancers has been at least in part due to lack of directed effort with an appreciation of free drug principles. At the same time, that CNS penetrant inhibitors of various kinases have been identified, and specifically designed and realized, demonstrates that success in this area can be achieved, even if the physicochemical properties of kinase inhibitors and those of CNS drugs at first appear at odds. The clear medical need, biological rationale, and improved appreciation for free drug principles provide an impetus and framework to properly approach the challenge of discovering and developing kinase inhibitors for brain cancer.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jmedchem.6b00618. Calculated physicochemical properties of FDA approved kinase inhibitors and of discussed inhibitors that are capable of penetrating the BBB or have limited CNS penetration (PDF)

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AUTHOR INFORMATION

Corresponding Author

*Phone: (650) 467-3214. E-mail: theff[email protected]. Notes

The author declares no competing financial interest. Biography Timothy P. Heffron is a Senior Scientist at Genentech. As a medicinal chemist and chemistry and research team leader, Timothy has contributed to the advancement of programs directed toward treatments for neurooncology, oncology (including cancer immunotherapy), neurology, and ophthalmology indications. Timothy has contributed to seven molecules that have advanced to clinical development, four of which came under his leadership as a chemistry team leader, including taselisib (phase III). Timothy completed his undergraduate studies in chemistry at Yale University and his doctoral studies at The Massachusetts Institute of Technology.

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ACKNOWLEDGMENTS Cyrus Khojasteh, Xingrong Liu, and Alan Olivero are acknowledged for their helpful comments in the preparation of this Perspective.

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ABBREVIATIONS USED GBM, glioblastoma multiforme; CNS, central nervous system; BBB, blood−brain barrier; CSF, cerebral spinal fluid; P-gp, P-glycoprotein; Bcrp, breast cancer resistance protein; HBD, hydrogen bond donor; TPSA, topological polar surface area; VEGFR, vascular endothelial growth factor receptor; PDGFR, platelet derived growth factor receptor; EGFR, epidermal growth factor receptor; PI3K, phosphoinositide 3-kinase; AKT, 10052



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Small Molecule Kinase Inhibitors for the Treatment of Brain Cancer

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