Fibroblast Growth Factor Receptor 4 (FGFR4 ... - ACS Publications

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Cite This: J. Med. Chem. XXXX, XXX, XXX−XXX

Fibroblast Growth Factor Receptor 4 (FGFR4) Selective Inhibitors as Hepatocellular Carcinoma Therapy: Advances and Prospects Miniperspective Xiaoyun Lu,*,†,∥ Hao Chen,†,∥ Adam V. Patterson,‡,§ Jeff B. Smaill,*,‡,§ and Ke Ding† †

School of Pharmacy, Jinan University, No. 601 Huangpu Avenue West, Guangzhou 510632, China Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand § Translational Therapeutics Team, Auckland Cancer Society Research Centre, School of Medical Sciences, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand

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‡

ABSTRACT: Hepatocellular carcinoma (HCC) is a lethal disease with limited therapeutic options and a particularly poor prognosis. Aberrant fibroblast growth factor 19 (FGF19) signaling through fibroblast growth factor receptor 4 (FGFR4) has been identified as an oncogenic driver for a subset of patients with HCC. FGFR4 is therefore a promising target for the treatment of HCC harboring aberrant FGF19FGFR4 signaling, and several FGFR4 inhibitors have advanced to clinical trial. In this review, we summarize the latest developments in FGFR4 inhibitors, including the known pharmacophores, their binding mode, selectivity, and clinical implications, as well as the optimization strategy of introducing an acrylamide into a known pan-FGFR inhibitor targeting Cys552 of FGFR4 to provide selective covalent FGFR4 inhibitors.

1. INTRODUCTION Hepatocellular carcinoma (HCC), accounting for 85−90% of primary liver cancer, is commonly associated with underlying chronic liver disease arising from viral infection, metabolic disorders, or alcohol abuse.1 HCC has become the sixth most common cancer worldwide with over 780 000 new cases diagnosed each year.2 HCC is refractory to conventional chemotherapy, and there has been minimal progress in the standard of care for the treatment of this disease in the past 20 years. The multikinase inhibitor sorafenib was approved for use in advanced HCC in 2007 based on a 3 month improvement in median survival and time to progression.3 In 2017, another multikinase inhibitor regorafenib was approved for the treatment of patients with HCC in Japan and the EU who have previously been treated with sorafenib.3 In the same year nivolumab was granted accelerated approval by the FDA for HCC patients previously treated with sorafenib, following reports of a 14.3% response rate in a 154-patient subgroup of the CHECKMATE-040 clinical trial (NCT01658878). Despite this encouraging progresses, there remains an urgent need to develop new therapies for HCC. Fibroblast growth factor receptor 4 (FGFR4) is a tyrosine kinase receptor that selectively binds fibroblast growth factor 19 (FGF19) to stimulate autophosphorylation in trans and mediates cellular effects via downstream MAP kinase and AKT signaling pathways.4,5 Aberrant signaling through the FGF19FGFR4 complex has been validated as an oncogenic driver of HCC.6,7 FGFR4 has therefore been considered as a novel potential target for the treatment of FGFR4-dependent © XXXX American Chemical Society

diseases, and in particular HCC. Several small molecule FGFR4 inhibitors with different selectivity profiles and binding modes have been developed and advanced to clinical trial for the treatment of HCC and other solid tumors harboring aberrant FGFR4 signaling.8,9 In this review, we focus on current developments in our understanding of the pharmacophores utilized, their binding modes and the kinome selectivity of current FGFR4 inhibitors. We further detail their clinical implications, with special attention paid to reversible covalent FGFR4 inhibitors. We also describe the medicinal chemistry optimization strategy utilizing the introduction of an acrylamide into a known pan-FGFR inhibitor targeting Cys552 of FGFR4 to provide selective covalent FGFR4 inhibitors.

2. FGF19/FGFR4 AND HCC FGFR4 is highly expressed in liver tissue and specifically utilizes endocrine FGF19 as its intracellular ligand.10 First, FGF19 binds to a binary complex formed by FGFR4 and βKlotho, a single-pass transmembrane co-receptor, leading to FGFR4 dimerization and autophosphorylation in trans.6,11 Subsequently, activated FGFR4 engages in the phosphorylation of FGF receptor substrate 2 (FRS2), leading to the recruitment of growth factor receptor-bound protein 2 (GRB2). By docking of adaptor proteins, the subsequent FGFR4 signaling complex may lead to the activation of four Received: October 1, 2018 Published: November 7, 2018 A

DOI: 10.1021/acs.jmedchem.8b01531 J. Med. Chem. XXXX, XXX, XXX−XXX

Journal of Medicinal Chemistry

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Figure 1. FGF19-FGFR4 mediated signaling pathway. FGF19 regulates cell functions by binding with its receptor FGFR4 and co-receptor βKlotho, leading to the activation of four signaling branches PI3K/AKT (depicted in yellow), PLCγ/DAG/PKC (green), RAS/RAF/MAPK (gray), and GSK3β/β-catenin (orange), which are involved in proliferation, antiapoptosis, angiogenesis, drug resistance, invasion, and epithelial-tomesenchymal transition (EMT) in HCC cells.

signaling branches PI3K/AKT, PLCγ/DAG/PKC, RAS/RAF/ MAPK, and GSK3β/β-catenin, which are involved in proliferation, antiapoptosis, angiogenesis, drug resistance, invasion, and epithelial-to-mesenchymal transition (EMT) in HCC cells (Figure 1). Nicholes et al. first demonstrated that overexpression of FGF19 at an ectopic site led to liver dysplasia and HCC in transgenic mice.12 Later, Wu et al. revealed that FGF19 increased hepatocyte proliferation by activating FGFR4 to induce HCC.13 In addition, FGF19 and its receptor FGFR4 have been shown to be involved in EMT in HCC cells through modulating the GSK3β/β-catenin signaling cascade.14 Moreover, it was found that downregulation of the FGFR4/FGF19 signaling pathway by small interfering RNA or by an autoinhibitory soluble domain (solFGFR4) led to decreased viability, invasion, and tumor formation of HCC in SCID mice.15 These data suggested that targeting FGF19/FGFR4mediated signaling provided a new promising strategy in HCC therapy.16

Figure 2. Schematic structure overview of FGFR4.

larger C-terminal domain composed of several α-helixes (Figure 3).19 The nonphosphorylated FGFR4 kinase is in an autoinhibited state, which is maintained by a hydrogen bond network termed a “molecular brake”.20 Sequence alignment of human FGFR4 and FGFR1/2/3 demonstrated that they share

3. STRUCTURE OF FGFR4 FGFR4 contains 802 amino acids composed of three immunoglobulin-like domains (D1−D3), a single-pass transmembrane domain, and a cytoplasmic intracellular split domain with tyrosine kinase function (Figure 2),17 which is conserved in the four FGFR subtypes. D1 and the acidic box, a unique sequence in the linker between D1 and D2, function as a receptor autoinhibition motif, while the D2 and D3 domains are vital for ligand binding and specificity (Figure 2).18 The intracellular kinase domain acts as an activator of downstream pathways by direct phosphorylation or recruitment of adaptor proteins. FGFR4 kinase domain has a typical protein kinase structure with two canonical domains: a smaller N-terminal domain composed of a five-stranded β sheet and the αC-helix, and a

Figure 3. Structural overview of a cocrystal structure of FGFR4 with BLU9931 (PDB code 4xcu). Expanded view is comparison of Cys552 in FGFR4 and Tyr 563 in FGFR1 (PD code 4v04). B



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Table 1. Classification and Representative FGFR4 Inhibitors classification Pan-FGFR inhibitors

FGFR4 selective inhibitors

name

organization

research status

LY2874455 JNJ42756493

Eli Lilly Janssen

Phase II Phase II

PRN1371 AZD4547 BGJ398

Principia Biopharma AstraZeneca Novartis

Phase I Phase II Phase II

Aminopyrazole BLU9931 BLU554 H3B-6527 FGF401 Aminopyrimidine Dipyridylamine

Novartis Blueprint Blueprint H3 Biomedicine Novartis GIBH and WuXi AppTec Novartis

Discovery Preclincal Phase I Phase I Phase I/II Candidate selected Discovery

clinical trial number NCT01212107 NCT02365597 NCT02699606 NCT02608125 NCT00979134 NCT01697605 NCT01975701

NCT02508467 NCT02834780 NCT02325739

Figure 4. (A) Chemical structure and pharmacophore of ponatinib. (B) Binding mode of ponatinib with FGFR4 (PDB code 4uxq). Hydrogen bonds are indicated by yellow dashed lines to key amino acids.

Figure 5. (A) Structure and pharmacophore of LY2874455. (B) Binding mode of LY2874455 with FGFR4 (PDB code 5JKG). Hydrogen bonds are indicated by yellow dashed lines to key amino acids.

74−92% sequence identity in the kinase domain;19 thus development of ATP-competitive FGFR4 isoform-selective inhibitors is challenging. However, one poorly conserved cysteine located at position 552 (Cys552) in the middle-hinge region of the ATP binding site of FGFR4 (corresponding tyrosine in FGFR1/2/3) has been exploited as a potential site to develop selective inhibitors of FGFR4 (Figure 3).21 In addition, another cysteine at position 477 of the P-loop of FGFR4 can also be a potential site for developing covalent pan-FGFR inhibitors due to its presence in all four FGFR subtypes.

4. SMALL MOLECULE INHIBITORS OF FGFR4 Given the contribution of FGFR4 signaling in HCC progression, clinical therapies are urgently needed to target the FGFR4 pathway. Several FGFR4 inhibitors have been evaluated in early phase clinical trials for the treatment of HCC and other cancers (Table 1). 4.1. Nonselective FGFR4 Inhibitors. 4.1.1. Multitargeted Kinase Inhibitors. Receptor tyrosine kinases (RTKs) possess a high sequence and structural homology in the kinase domain. To date, several known multitargeted RTK inhibitors have been studied for the suppression of FGFR signaling, such as ponatinib,22 nintedanib,23 dovitinib,24 and lucitanib.25 The multikinase inhibitor ponatinib by way of an example (Figure C



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Figure 6. (A) Structure and pharmacophore of JNJ-42756493. (B) Binding mode of JNJ-42756493 with FGFR1 (PDB code 5EW8). Hydrogen bonds are indicated by yellow dashed lines to key amino acids.

nitrogen forming a hydrogen bond with Asn557. In addition, the ethoxyl substituted 2-vinylpyrazolyl group is directed toward solvent accessible space. LY2874455 is being evaluated in phase II clinical trial by Eli Lilly for the treatment of patients with advanced cancer (NCT01212107). 4.1.2.2. JNJ-42756463. Like LY2874455, JNJ-42756493 (3, erdafitinib) is also a potent inhibitor of the FGFR1/2/3/4 isoforms with similar IC50 values of 1.2, 2.5, 3.0, and 5.7 nM, respectively (Figure 6A),30 while it also inhibited VEGFR2 with an IC50 value of 36.8 nM. Publication of an FGFR1/JNJ42756493 X-ray cocrystal structure provided a detailed binding interaction conserved across the other FGFR isoforms (Figure 6B).31 Counterscreening against 451 kinases (KINOMEscan) indicated the low selectivity of JNJ-42756493 might lead to side effects due to off-target action. Nevertheless, JNJ42756493 exhibited potent in vitro and in vivo anticancer activity against tumors with activating FGFR alterations. JNJ42756463 is now in phase II trial for the treatment of metastatic or surgically unresectable urothelial cancer (NCT02365597) and non-small cell lung cancer, gastric cancer, esophageal cancer, and cholangiocarcinoma (NCT02699606). Janssen Pharmaceuticals has recently announced that JNJ-42756493 has been granted breakthrough therapy designation by FDA for the treatment of metastatic urothelial cancer. 4.1.2.3. PRN1371. Unlike LY2874455 and JNJ-42756493, PRN1371 (4) is an irreversible (or covalent) pan-FGFR inhibitor designed to covalently bind a conserved cysteine located on the p-loop of FGFR1−4 (numbered Cys477 in FGFR4) (Figure 7).32 PRN1371 exhibited strong potency against FGFR1/2/3/4 with IC50 values of 0.7, 1.3, 4.1, and 19.3 nM, respectively, while sparing VEGFR2 (IC50 = 705 nM). PRN1371 also displayed excellent kinome-wide selectivity and potency against cancer cells harboring FGFR alterations.33 Moreover, PRN1371 had favorable PK characteristics and sustained FGFR inhibition in vivo following clearance of drug from circulation. Thus, PRN1371 exhibited strong activity in multiple tumor xenografts and patientderived tumor xenograft (PDX) models driven by FGFR alterations. PRN1371 is in phase I clinical development under sponsorship of Principia Biopharma for the treatment of solid tumors (NCT02608125). 4.1.2.4. Aminopyrazole. Novartis reported an optimization strategy directed toward improved FGFR4-selectivity involving introduction of an acrylamide into the pan-FGFR inhibitor scaffold of AZD4547 (5).34 Aminopyrazole 6 (Figure 8),

4A) has been approved for the treatment of patients with resistant or intolerant chronic myeloid leukemia (CML) and Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) by virtue of targeting ABL kinase.26 In 2012, ARIAD Pharmaceuticals also reported ponatinib inhibited the in vitro kinase activity of FGFR1/2/3/4 with IC50 values of 2, 2, 18, and 8 nM, respectively.22 X-ray structural analysis of a ponatinib/FGFR4 complex confirmed ponatinib bound to FGFR4 with a type II binding mode and maintained a network of protein contacts similar to those observed when binding ABL kinase (Figure 4B).19,27 The imidazo[1,2-b]pyridazine core makes a hydrogen bond with Ala553, the amide linker forms two hydrogen bonds with Glu520 and Asp630, and the trifluoromethylphenyl group binds deeply into the hydrophobic pocket. Further cellular assays and in vivo studies suggested that ponatinib may serve as a potential treatment for FGFR-driven solid tumors.22 However, the toxicity profile of ponatinib related to on-target activity against the VEGF receptors restricts its further development for the treatment of HCC.2 In this regard, it has been suggested that more selective FGFR inhibitors may have the potential to display an improved therapeutic margin relative to multitargeted RTK inhibitors. 4.1.2. Pan-FGFR Inhibitors. The reported clinical panFGFR inhibitors with potent FGFR4 inhibitory activity (LY2874455, JNJ-42756463 and PRN1371) are shown in Table 1. Some others with relatively weak FGFR4 inhibitory activity (AZD4547and BGJ398) are not described here. 4.1.2.1. LY2874455. LY2874455 (2) is a pan-FGFR inhibitor with low nanomolar potency in biochemical assays against all four FGFR isoforms (IC50 values of 2.8, 2.6, 6.4, and 6 nM for FGFR1/2/3/4, respectively) (Figure 5A), whereas is about 6- to 9-fold less potent against VEGFR2.28 LY2874455 discovery was based on a novel indazole scaffold, but the detailed SAR studies have not yet been reported. It exhibits potent inhibition of multiple cancer cell lines mediated by FGF/FGFR signaling (IC50 = 0.57−290.7 nM). Further, LY2874455 displays potent in vivo anticancer activity in several tumor xenograft models without evidence of off-target VEGFR2-mediated toxicities. An X-ray crystal structure of LY2874455 with FGFR4 demonstrated LY2874455 is a type I inhibitor that binds to the DFG-in active conformation of FGFR4 with conserved interactions as for FGFR1/2/3 (Figure 5B).29 Briefly, the indazolyl ring forms two hydrogen bonds with hinge residues Glu551 and Ala553, while the dichloropyridinyl ring occupies a hydrophobic pocket with the pyridyl D



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serious toxicity, requiring strategies that mitigate plasma phosphate increases, has been attributed to on-target systemic inhibition of FGFR1 and FGFR3, leading to blockade of FGF23 mediated signaling disrupting normal phosphate homeostasis.39 Hence, compounds that are able to selectively target FGFR4 while sparing its isoforms (FGFR1/2/3) may demonstrate an improved therapeutic margin and may therefore be of significant promise. However, given the high sequence homology between the ATP-binding pockets of the FGFR family, developing FGFR4 selective inhibitors represents a major challenge in oncology. To this end, several classes of FGFR4 selective inhibitors that target the unique cysteine 552 have been reported (Figure 3). 4.2.1. Irreversible Inhibitors. 4.2.1.1. BLU9931 and BLU554. With the aim of discovering FGFR4 selective inhibitors, Blueprint Medicines developed a series of compounds based on an anilinoquinazoline scaffold utilizing structure-based design methods to covalently target Cys552 in the hinge region of FGFR4 (Figure 9).21 Briefly, inspired by the high potency and good selectivity of the pan-FGFR inhibitor PD173074 (7), a 2,6-dichloro-3,5-dimethoxyphenyl group (8) was introduced instead of the dimethoxyphenyl moiety of 7 to occupy the hydrophobic back pocket. Further optimization of the aniline ring included introduction of an electrophilic acrylamide at the ortho-position (9) that was capable of forming a covalent bond with Cys552 in FGFR4. However, possibly due to the undesirable rotational angle between the aniline group and the quinazoline core, compound 9 did not exhibit the desired selectivity for FGFR4. Thus, a methyl group was introduced at the remaining ortho-position of the aniline ring to increase the rotation of this ring out of plane with the quinazoline core, leading to BLU9931 (10). An X-ray crystal structure of FGFR4 and BLU9931 revealed that the aminoquinazoline core formed two hydrogen bonds with the hinge region Ala553 while the acrylamide successfully formed a covalent bond with Cys552 to achieve potent FGFR4 activity and the desired selectivity over FGFR1/2/3 (Figure 10). In addition, the dichlorodimethoxyphenyl group occupied the hydrophobic pocket in a similar manner to the known panFGFR inhibitors. BLU9931 demonstrated potent FGFR4 activity (IC50 = 3 nM) with good selectivity over FGFR1/2/3 (IC50 = 591, 493, and 150 nM, respectively). BLU9931 also displayed excellent kinome-wide selectivity and inhibited the proliferation of HCC cell lines with an activated FGFR4 signaling pathway. BLU9931 induced apoptosis in Hep3B human liver cancer cells and significantly inhibited growth of Hep3B tumor xenografts in nude mice at 100 and 300 mg/kg po b.i.d. with

Figure 7. Structure and pharmacophore of PRN1371.

designed to target Cys552 unique to FGFR4, unfortunately lacked the FGFR4-selectivity sought, instead displaying potent inhibitory activity against FGFR1/2/3/4 (IC50 = 1.5, 4.5, 2.2, and 1.7 nM, respectively). Further biochemical analysis demonstrated that compound 6 was 400-fold less active against FGFR4C477A when compared to FGFR4 wild type, whereas a loss of only 5-fold in activity was observed with FGFR4C552A, which strongly supports Cys447 (common to all four isoforms) as the primary site of covalent reaction of 6 with FGFR4.35 An X-ray crystal structure of compound 6 with FGFR4 was determined to further clarify its binding mode. The aminopyrazole core was found to form three hydrogen bonds with the hinge residues Ala553 and Glu551 in the proximity of Cys552. The acrylamide moiety was determined to form a covalent bond with Cys477. In addition, the dimethoxyphenyl group occupied the hydrophobic pocket with an additional hydrogen bond to Asp630. The positioning of the aminopyrazole core in the hinge region and the formation of an intramolecular hydrogen bond between the N−H of the acrylamide and carbonyl group of the inhibitor phenyl carboxamide support formation of two hydrogen bonds between the acrylamide carbonyl and Asn557, features of the binding mode that all serve to position the acrylamide Michael acceptor toward Cys477. 4.2. Selective FGFR4 Inhibitors. Collectively, early trials of several pan-FGFR inhibitors have proven encouraging for the treatment of patients with various FGFR fusions, including muscle-invasive urothelial carcinoma, glioma, and biliary tract cancers including cholangiocarcinomas.36 However, hyperphosphatemia is a commonly observed adverse effect for panFGFR inhibitors such as JNJ-4275649337 and BGJ398.38 This

Figure 8. (A) Optimization strategy of compound 6. (B) Binding mode of 6 with FGFR4 (PDB code 5nwz). Hydrogen bonds are indicated by yellow dashed lines to key amino acids. E



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Figure 9. Optimization process of BLU9931 and BLU554.

rate of 68%.41 The most common and more serious grade 3−4 side effects are anemia, diarrhea, and elevations in liver enzymes (ALT and AST). 4.2.1.2. H3B-6527. H3 Biomedicine has developed the FGFR4 selective irreversible inhibitor H3B-6527 (13)42,43 by incorporating an acrylamide into the ortho-position of the aniline group of the Novartis pan-FGFR inhibitor BGJ398 (12) to target Cys552 of FGFR4 (Figure 11A). The acrylamide moiety not only increased the binding affinity to FGFR4 but also induced a steric clash with the corresponding Tyr residue of FGFR1−3, improving FGFR4 selectivity. H3B6527 selectively inhibits FGFR4 (IC50 < 1.2 nM) while sparing FGFR1/2/3 (IC50 = 0.32, 1.29, and 1.06 μM, respectively) and other kinases. Subsequently, both FGFR4 mass spectrometry and FGFR1-Y563C protein X-ray crystallography studies confirmed the covalent binding of H3B-6527 to the target cysteine. In this instance an FGFR1 surrogate crystallization system in which the key Tyr563 of FGFR1 is mutated to cysteine (Cys563) was used to mirror the ATP-binding pocket of FGFR4 and interrogate the binding mode of H3B-6527 by X-ray crystallography (Figure 11B). The aminopyrimidine core forms two hydrogen bonds with the hinge residue Ala564, and the dichlorodimethoxyphenyl group occupies the hydrophobic pocket forming an additional hydrogen bond with Asp641. H3B-6527 exhibited excellent antitumor activity against FGF19-amplified HCC cell lines and HCC PDX models.43 Preclinical studies also revealed that FGF19 expression was a predictive biomarker for H3B-6527 response. Moreover, administration of H3B-6527 combined with palbociclib

Figure 10. Binding mode of BLU9931with FGFR4 (PDB code 4xcu). Hydrogen bonds are indicated by yellow dashed lines to key amino acids.

no significant changes in body weight. BLU9931 represents a first-in-class irreversible selective FGFR4 inhibitor for the treatment of HCC patients with aberrant FGFR4 signaling. However, BLU9931 has not entered clinical study. Further optimization of BLU9931 with the aim of improving its physicochemical properties afforded the clinical candidate BLU554 (11).40 BLU554 is currently in phase I clinical trials for the treatment of hepatocellular carcinoma (NCT02508467) and has also been granted orphan drug designation by FDA in 2015. An interim analysis of the phase I study reports that BLU554 is efficacious in HCC patients with an overall response rate (ORR) of 16% and a disease control

Figure 11. (A) Optimization strategy of H3B-6527. (B) Binding mode of H3B-6527 with FGFR1-Y563C (PDB code 5vnd). Hydrogen bonds are indicated by yellow dashed lines to key amino acids. F



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and high plasma clearance in an in vivo PK study. Further optimization of the 2-aminopyrimidine series is ongoing. 4.2.1.4. Dipyridylamine. Novartis have reported another electrophile variation designed to achieve covalent binding with Cys522 of FGFR4, a 3-nitro-6-chloropyridyl moiety, in which the 6-chloro substituent is positioned for attack by the Cys552 thiomethyl group through a SNAr nucleophilic aromatic substitution (Figure 14). The dipyridylamine 18

synergistically suppressed tumor growth in a xenograft model of HCC. H3B-6527 is currently in phase I clinical trial for advanced HCC and intrahepatic cholangiocarcinoma (NCT02834780), having been granted an orphan drug designation by the U.S. FDA for the treatment of HCC in 2017. Thus, we conclude that structure-based design of selective FGFR4 inhibitors by incorporating a Michael acceptor on a pan-FGFR inhibitor scaffold is of significant interest. 4.2.1.3. Aminopyrimidine. Our group recently reported a series of 2-aminopyrimidine compounds as selective FGFR4 inhibitors based on a ring opening strategy designed to eliminate the benzene ring of BLU9931 (Figure 12).44

Figure 14. (A) Chemical structure of dipyridylamine 18. (B) Binding mode of 18 with FGFR4 (PDB code 5nud). Hydrogen bonds are indicated by yellow dashed lines to key amino acids.

Figure 12. Optimization strategy of 2-aminopyrimidine 14.

was identified by high throughput screening (HTS), demonstrating high potency against FGFR4 (IC50 = 53 nM) while sparing the FGFR1−3 isoforms (IC50 > 10 μM) (Figure 14A).34 Subsequent mass spectrometry and protein X-ray crystallography confirmed covalent interaction with FGFR4. In addition, it was found that each pyridyl ring nitrogen atom formed a hydrogen bond with hinge residue Ala553. The relatively low molecular weight and novel mechanism of covalent binding of dipyridylamine 18 suggest potential as a promising lead compound for further discovery of FGFR4 selective inhibitors. 4.2.2. Reversible Inhibitors. 4.2.2.1. Reversible Covalent Inhibitors. Concerns about potentially undesirable side effects from irreversible-covalent inhibition due to nonspecific reactivity with off-target proteins and the immunogenic nature of small molecule/protein adducts, together with the observation that HCC cell lines demonstrate a relatively fast FGFR4 resynthesis rate ( 10 μM). Compound 14 also exhibited extraordinary target specificity in a kinome-wide screen and selectively suppressed proliferation of breast cancer cells harboring an FGFR4Y367C mutation. However, the poor pharmacokinetic (PK) properties of compound 14 limited its potential for in vivo studies. WuXi AppTec also reported a series of aminopyrimidine compounds deriving from the structure-based drug design strategy of adding a phenylacrylamide moiety to the core structure of pan-FGFR inhibitor ASP5878 (Figure 13).45 The first hybrid compound 16 showed ideal FGFR isoform selectivity with an IC50 of 3 nM against FGFR4 and >8 μM against FGFR1. Compound 16 displayed better physicochemical properties than BLU9931 but unfortunately suffered from poor plasma and microsomal stability with a high Clint(liver) value of 9643 mL min−1 kg−1 in mouse liver microsomes. Further optimization of 16 with the aim of improving plasma stability afforded compound 17, which maintained both FGFR4 inhibitory potency and selectivity. Unfortunately, compound 17 still displayed a low volume of distribution

Figure 13. Optimization process of 2-aminopyrimidine 17. G



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Figure 15. Optimization process of FGF401 and its analogue 23.

Further medicinal chemistry optimization of hit 19 yielded a more potent tetrahydronaphthyridine urea 20 to improve the solubility of the compound by reducing the aromatic planar nature of 19 without disrupting the intramolecular hydrogen bond between the amide/urea N−H and the quinoline nitrogen.46 Molecular modeling indicated that 20 covalently bound the FGFR4 ATP binding pocket with the aminopyridyl moiety forming two hydrogen bonds with hinge residues Glu551 and Ala553. FGFR4 kinetic binding studies showed compound 20 possessed a long target residence time (4.5 h). Systematic SAR investigations at the aminopyridyl moiety and the tetrahydronaphthyridine scaffold led to the drug candidate FGF401 (22) with high potency and ideal physical properties.47 FGF401 displayed at least 1000-fold selectivity for FGFR4 over FGFR1/2/3 and other kinases,48 with an IC50 value of 1.9 nM against FGFR4. Moreover, FGF401 has remarkable antitumor activity in mice bearing HCC tumor xenografts and PDX models as well as excellent pharmacokinetic/ pharmacodynamics (PK/PD) properties.49 FGF401 has entered phase I/II clinical trial to evaluate its safety and efficacy in HCC and other solid tumors characterized by positive FGFR4 and β-klotho expression (NCT02325739). Recently, researchers at Novartis found that FGF401 led to upregulation of bile acid synthesis correlated to a subsequent increase in ALT expression in preclinical safety studies, which can be prevented by combination with the bile acid sequestrant cholestyramine.50 In 2018, HANSOH Pharma also patented a series of 2-formylpyridyl ureas with a similar structure to FGF401 (example as 23).51 4.2.2.2. Reversible Inhibitors. The smaller residue volume of Cys552 in FGFR4 when compared to the corresponding tyrosine of FGFR1/2/3 provides an opportunity for designing selective inhibitors of FGFR4. Analysis of the Novartis internal kinase panel revealed that an isopropoxy substituted diaminopyrimidine compound (24) displayed more than 100-fold selectivity for FGFR4 over FGFR1/2/3 (Figure 16).34 Binding mode analysis indicated that the isopropoxy group filled a small hydrophobic pocket formed by Cys552 in FGFR4; however this substituent could not be accommodated by FGFR1/2/3 due to the larger tyrosine residue size. Subsequent replacement of the isopropoxy group with the

Figure 16. Optimization of the reversible selective FGFR4 inhibitors 24 and 26.

smaller methoxy group led to compound 25, which lost FGFR4 selectivity due to this substituent being well accommodated in the hinge region of FGFR1/2/3/4. Further medicinal chemistry optimization of substituents on the phenyl ring coupled with variations in structure predicted to occupy the aromatic ring binding back pocket provided an improved derivative 26, which maintained FGFR4 potency and selectivity. Similar to 24, the isobutoxy group formed key hydrophobic interactions with Cys552 while the aminopyrimidine core made the specific hydrogen bond contacts with the hinge residue Ala553. In addition to these interactions the introduced bicyclic moiety extended into the hydrophobic back pocket created by Val481 and Gly474.34

5. PERSPECTIVE AND CONCLUSIONS FGF19/FGFR4 mediated signaling plays a functional role in hepatocellular carcinoma (HCC) progression and metastasis, making FGFR4 a promising target for discovery of new drugs for the treatment of HCC. Numerous classes of small molecule FGFR4 inhibitors with differing selectivity profiles have been discovered, and several have been advanced to clinical trial. However, some of the early clinical candidates discussed herein were originally developed to target FGFR1/2/3 and lack FGFR4 isoform selectivity (pan-FGFR inhibitors). These H



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agents have demonstrated on-target FGFR1/3 dose-related limiting toxicities, such as hyperphosphatemia, which required strict phosphate management protocols and limited their clinical utility. Encouragingly, several classes of highly selective FGFR4 inhibitors have recently been designed by targeting a poorly conserved cysteine found in the ATP-binding domain of FGFR4 (Cys552). Both BLU554 and H3B-6527 that utilize this approach are in phase I clinical trials for the treatment of HCC. Interim results indicate the promising potential for FGFR4-based HCC therapy. However, recent studies also demonstrate that the fast resynthesis rate of FGFR4 in HCC cells will require an inhibitor with a toxicity profile that allows for frequent dosing to achieve complete and continuous target inhibition to reach maximum antitumor efficacy. Reversible-covalent inhibitors of FGFR4 may theoretically have the necessary properties required. The recently disclosed FGFR4 reversible-covalent inhibitor FGF401, which binds to Cys552 through an aldehyde group to generate a hemithioacetal adduct, shows remarkable antitumor activity in preclinical studies and has now entered phase I/II clinical evaluation. Despite the significant progress made in the design and development of selective FGFR4 inhibitors, two major limitations and challenges remain. (1) As with other tyrosine kinase inhibitors, a growing challenge for FGFR4 inhibitor efficacy is the development of acquired resistance. The gatekeeper mutations FGFR4V550L and FGFR4V550M have been identified.52 The pan-FGFR inhibitor FIIN-2 has been reported to have activity against the FGFR4V550L mutation, but this agent has low or no selectivity for FGFR4 relative to the other FGFR isoforms.53 With this recognized mechanism of resistance and other induced acquired resistance mutations expected, development of FGFR4 inhibitors with high selectivity and potency for predicted mutants is critical. (2) The reported irreversible or reversible-covalent inhibitors are capable of selectively inhibiting FGFR4 but are still in early clinical trials. The evaluation of more chemotypes in comprehensive clinical studies with a clear focus on selection of appropriate patients and predictive biomarkers of response is needed to fully validate the use of FGFR4 selective inhibitors for the treatment of HCC with aberrant FGFR4 signaling.

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medicinal chemistry and combined computational methods for lead optimization. Hao Chen received his Bachelor degree at Shenyang Pharmaceutical University, China. He is currently study for his Master degree at Jinan University. His recent academic work is focused on synthesis kinase inhibitors as anticancer drugs. Adam V. Patterson was educated at Oxford University where he completed his Bachelor of Biochemistry degree. He undertook his doctoral training jointly at the MRC Radiobiology unit and Institute of Molecular Medicine, Oxford, where he researched various prodrug therapies. After completing a postdoctoral fellowship at the University of Manchester he joined the Faculty of Medical and Health Sciences at the University of Auckland. He is currently an Associate Professor and leads the Translational Therapeutics Team, a talented group of scientists within the Auckland Cancer Society Research Centre. His core interests are focused on translational cancer therapeutics, including drug discovery and development, specializing in the tumour microenvironment as a therapeutic target. Jeff B. Smaill received his Ph.D. in Organic Chemistry from the University of Otago and did his postdoctoral training at the University of Cambridge. He is currently an Associate Professor at the University of Auckland where he leads a medicinal chemistry group at the Auckland Cancer Society Research Centre in the Faculty of Medical and Health Sciences. He is an Associate Investigator of the Maurice Wilkins Centre for Molecular Biodiscovery, one of New Zealand’s 10 Centres of Research Excellence. He has had 25 years of experience leading drug discovery programs in collaboration with industry partners. His research interests include the discovery of novel small molecule irreversible kinase inhibitors and hypoxia-activated prodrugs. He has been involved in the development of canertinib, dacomitinib, tarloxotinib, and CP-506. Ke Ding is Professor of Medicinal Chemistry at Jinan University. He obtained his Ph.D. from Fudan University in 2001 and did his postdoctoral trainings at University of Michigan, Ann Arbor. Dr Ding worked as a professor at Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences during 2006−2016. Dr. Ding’s research interests mainly focus on design and synthesis of novel bioactive lead compounds for drug discovery. He has published more than 160 publications and is co-inventor of over 50 international patents, some of which have been licensed to international pharmaceutical companies.

AUTHOR INFORMATION

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Corresponding Authors

ACKNOWLEDGMENTS The authors appreciate the financial support from National Natural Science Foundation of China (Grants 81874285 and 81673285), Outstanding Youth Fund of Guangdong (Grant 2015A030312014), Cancer Society Auckland Northland, and Jinan University.

*X. L.: e-mail, [email protected]; phone, +86-2085223259; fax, +86-20-85224766. *J.B.S.: e-mail, [email protected]; phone, +64-99236798. ORCID

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Xiaoyun Lu: 0000-0001-7931-6873 Ke Ding: 0000-0001-9016-812X

ABBREVIATIONS USED FGFR4, fibroblast growth factor receptor 4; FGF19, fibroblast growth factor 19; HCC, hepatocellular carcinoma; Cys, cysteine; EU, European Union; EMT, epithelial−mesenchymal transition; GSK3β, glycogen synthase kinase 3β; FRS2, FGFR substrate 2; GRB2, growth factor receptor-bound 2; PI3K, phosphatidylinositol 4,5-bisphosphate 3-kinase; AKT, protein kinase B; PLCγ, phospholipase C-γ; DAG, diacylglycerol; PKC, protein kinase C; MAPK, mitogen-activated protein kinase; CML, chronic myeloid leukemia; ALL, acute lymphoblastic leukemia; RTK, receptor tyrosine kinase; SAR, structure−activity relationship; PDX, patient-derived tumor

Author Contributions ∥

X.L. and H.C. contributed equally to this work.

Notes

The authors declare no competing financial interest. Biographies Xiaoyun Lu is Professor of Medicinal Chemistry at Jinan University. She received her Ph.D. from China Pharmaceutical University in 2010 and then worked at Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences during 2010−2016. Dr Lu’s research is mainly focused on discovering novel small molecule kinase inhibitors for anticancer and anti-inflammatory therapy using synthetic I



Perspective

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xenograft; ORR, overall response rate; ALT, alanine aminotransferase; AST, aspartate aminotransferase; HTS, high throughput screening; GIBH, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences

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