Editorial Cite This: ACS Med. Chem. Lett. 2018, 9, 513−514
Current Innovations in Medicinal Chemistry and Chemical Biology erriam−Webster defines innovation as a “a new idea, method, or device”. However, innovation is often also viewed as the application of better solutions that meet new requirements, unarticulated needs, or existing market needs. In this special issue of ACS Medicinal Chemistry Letters we have solicited and selected articles that should be of significant interest to readers in the medicinal chemistry community and ones that we believe demonstrate interesting and innovative approaches to problems/topics of current interest. In the medicinal chemistry area, especially in pharmaceutical research, chemists spend a considerable amount of time optimizing drug pharmacokinetics including half-life, clearance, volumes of distribution, etc. In this issue, we have two back to back articles that deal with potential best practices. The article from Brocatelli et al. on “Why Decreasing Lipophilicity Alone Is Often Not a Reliable Strategy for Extending IV Half-Life” presents an extensive analysis of Genentech’s in vitro and in vivo rat pharmacokinetic data, which highlights how half-life optimization through simple modulation of lipophilicity is generally not a successful strategy. Decreasing lipophilicity without addressing a metabolic softspot will often lead to both lower clearance and volume of distribution without extending half-life. The related article from Gunaydin et al. from Merck on “Strategy for Extending HalfLife in Drug Design and Its Significance” posit that the relationship between dose and half-life is nonlinear when unbound clearance kept constant, whereas the relationship between dose and unbound clearance is linear when half-life kept constant. Due to this difference, they show that dose is more sensitive to changes in half-life than changes in unbound clearance when half-lives are shorter than 2 h. Through matched molecular pair analyses, they also show that the strategic introduction of halogens is likely to increase half-life and lower projected human dose even though increased lipophilicity does not guarantee extended half-life. In the new therapies arena Joe Sweeney et al. in their Letter “Riluzole−Triazole Hybrids as Novel Chemical Probes for Neuroprotection in Amyotrophic Lateral Sclerosis Using Primary Cortical Neurons as a Test Vehicle” delineate that, despite intense attention from biomedical and chemical researchers, there are few approved treatments for amyotrophic lateral sclerosis (ALS), with only riluzole (Rilutek) and edaravone (Radicava) currently available to patients. Moreover, the mechanistic basis of the activity of these drugs is currently not well-defined, limiting the ability to design new medicines for ALS. Their Letter describes the synthesis of triazole containing riluzole analogues, and their testing in a novel neuroprotective assay. The “Synthesis of Thymoquinone− Artemisinin Hybrids: New Potent Antileukemia, Antiviral, and Antimalarial Agenst” by Tsogoeva et al. described a series of hybrid compounds based on the natural products artemisinin and thymoquinone that were synthesized and investigated for their biological activity against the malaria parasite Plasmodium falciparum, human cytomegalovirus (HCMV), and two leukemia cell lines (drug-sensitive CCRF-CEM and multi-
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drug-resistant subline CEM/ADR5000). An unprecedented one-pot method of selective formation of C-10α-acetate 14 starting from a 1:1 mixture of C-10α- to C-10β-dihydroartemisinin (DHA) was developed. Ether-linked thymoquinone− artemisinin hybrids stood out as the most active compounds in all categories, while showing no toxic side effects toward healthy HFFs and thus being selective. They exhibited EC50 values of 0.2 μM against the doxorubicin-sensitive as well as the multidrug-resistant leukemia cells and therefore can be regarded as superior to doxorubicin. Overall, most of the presented thymoquinone−artemisinin based hybrids exhibited an excellent and broad variety of biological activities (anticancer, antimalarial, antiviral) combined with a low toxicity/high selectivity profile. Considerable interest within academia has arisen over the past few years in identifying small molecule regulators of mRNA and microRNA (miRNA) function with significant contributions from Matt Disney and Kevin Weeks among others. Amanda Garner’s group at Michigan, in the Featured Letter “Expansion of cat-ELCCA for the Discovery of Small Molecule Inhibitors of the prelet-7−Lin28 RNA−Protein Interaction”, describe that the dysregulation of miRNA expression has been linked to many human diseases; however, because of the challenges associated with RNA-targeted drug discovery, additional approaches are needed for probing miRNA biology. The emerging regulatory role of miRNAbinding proteins in miRNA maturation presents such an alternative strategy. Exploiting their laboratory’s click chemistry-based high-throughput screening (HTS) technology, a catalytic enzyme-linked click chemistry assay (cat-ELCCA), they designed a modular method by which to discover new chemical tools for manipulating pre-miRNA−miRNA binding protein interactions. Using the prelet-7d−Lin28 interaction as proof-of-concept, the results presented demonstrated how HTS using cat-ELCCA can enable the discovery of small molecules targeting RNA−protein interactions. Elucidation of compound selectivity and target engagement in cells remains an area of considerable interest to the Pharmaceutical Industry and others. Chemical proteomic approaches remain in vogue, and in the paper entitled “Chemical Proteomic Characterization of a Covalent KRASG12C Inhibitor” from Mike Chalmers et al. from Lilly, the team targets the KRASG12C protein product, which is an attractive, yet challenging, target for small molecule inhibition. One option for therapeutic intervention is to design small molecule ligands capable of binding to, and inactivating KRASG12C, via formation of a covalent bond to the sulfhydryl group of cysteine 12. In order to better understand the cellular off-target interactions of Compound 1, a covalent KRASG12C inhibitor, they completed a series of complementary chemical proteomics experiments in H358 cells. A new thiol reactive probe (TRP) was designed and used to construct a cellular Special Issue: Med Chem Tech: Driving Drug Development Published: June 14, 2018 513
DOI: 10.1021/acsmedchemlett.8b00252 ACS Med. Chem. Lett. 2018, 9, 513−514
ACS Medicinal Chemistry Letters
Editorial
medicinal chemistry depends on the continued ability to identify and integrate innovative solutions that enable pursuit of novel frontiers of drug discovery.
target occupancy assay for KRASG12C, and in addition, the thiol reactive probes allowed them to profile potential off target interactions of compounds with over 3200 cysteine residues. Another technique that is used quite frequently to establish target engagement in a label-free manner is CETSA. To address the need for specific antibodies for the target of interest, as well as challenges with detecting low abundance proteins, in the Letter titled “Homogeneous Assay for Target Engagement Utilizing Bioluminescent Thermal Shift”, Melanie Dart et al. from Promega report NanoLuc luciferase TSA (NaLTSA). This method involves genetically fusing the small (19 kDa) NanoLuc (Nluc) luciferase to the target protein(s) of interest. The utility of NaLTSA for assessing target engagement of molecules to a diverse set of target classes such as kinases, bromodomains, and histone deacetylases, as well as selectivity of a particular compound against a collection of targets has been demonstrated. Continuing the theme of medicinal chemistry developments at the intersection of chemistry and biology, Cravatt et al. demonstrate the versatility of activity based protein profiling (ABPP) by identifying a class of N-hydroxyhydantoin (NHH) carbamates that potently inhibit NOTUM, a serine hydrolase that deactivates Wnt proteins, in their Letter entitled “Potent and Selective Irreversible Inhibitors of the Wnt-Deacylating Enzyme NOTUM Developed by Activity-Based Protein Profiling”. MS-ABPP methods indicate that this class of inhibitors demonstrate very good selectivity against 64 other serine hydrolases and counteract the suppression of Wnt signaling by NOTUM in cellular assays. Extension of these probes via installation of suitable reporter groups further demonstrated the selective labeling of NOTUM in lysates. These small molecule tools should prove to be useful to interrogate the functional consequences of NOTUM modulation in various disease settings. There has been considerable interest of late to better characterize the permeability of “beyond rule of 5” compounds. Continuing the theme of new applications to understand compound properties, in the Letter entitled “AzithromycinInduced Changes to Bacterial Membrane Properties Monitored in Vitro by Second-Harmonic Light Scattering”, Wilhelm and co-workers demonstrate the application of time-resolved second-harmonic light scattering (SHS) to quantify azithromycin-induced changes to bacterial membrane permeability. A proposed biophysical phenomenon whereby AZM induces localized thinning of the membrane and the temporal relationship to enhanced permeability is presented. Induced protein degradation (Protacs, Degronimids, SNIPERs) has the potential to be a disruptive modality of therapeutic intervention. In the Letter entitled “Development of Highly Potent and Selective Steroidal Inhibitors and Degraders of CDK8”, Gray and co-workers report the discovery of a steroid-based scaffold as a structurally simplified version of Cortistatin A with potent CDK8 inhibition. Conversion of these inhibitors into CDK8 degraders was achieved by varying the linker length between the steroid scaffold and Pomalidomide, a Cereblon binder. Differential selectivity between targets degraded and inhibited was observed, as well as the reliance on the proteasome for CDK8 degradation. In conclusion, we hope that this issue stimulates interest in various emerging chemistry and chemical biology techniques aimed at enhancing the probability of technical success of therapeutic modalities that could have a remarkable impact on patients’ lives. We fervently believe that the future success of
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Stevan W. Djuric Anil Vasudevan AUTHOR INFORMATION
ORCID
Anil Vasudevan: 0000-0002-0004-0497 Notes
Views expressed in this editorial are those of the authors and not necessarily the views of the ACS.
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DOI: 10.1021/acsmedchemlett.8b00252 ACS Med. Chem. Lett. 2018, 9, 513−514
