Discovery of a “First-in-Class” Selective Multikinase (CDK4/6/9-AURKA/B) Inhibitor, LCI133, for Neuroblastoma
https://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.5c01688
Abstract
Our central hypothesis in this report is that the development of a single small molecule inhibitor that binds to multiple targets will be safer and more efficacious against high-risk cancers which rapidly develop resistance to one targeted therapeutic agent. We used a rational pharmacophore merging strategy and X-ray crystal structures of CDK6, CDK9, and AURKA to discover LCI133, a “first-in-class” nanomolar (nM) potent CDK4/6/9-AURKA/B inhibitor. Selectivity profiling of LCI133 using the scanMAX kinome assay of 468 kinases revealed that it is highly selective for CDK4/9 and AURKA targets. Pharmacokinetic studies with LCI133-HCl in mice demonstrate a high systemic exposure (AUC) of 7812 ng × h/mL and maximum plasma concentration (Cmax) of 3305 ng/mL. Neuroblastoma (NB) cells displayed nM sensitivity to LCI133 in vitro, and we observed potent antitumor effects in vivo in a BE(2)-C neuroblastoma xenograft model, without overt toxicity and an increase in the overall survival rate.
Discovery and Optimization of a Non-Nucleoside-Based Series of Inhibitors of 2′-Deoxynucleoside 5′-Monophosphate Glycosidase (DNPH1)
https://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.5c02356
Abstract
DNPH1 is a nucleotide pool sanitizer that cleaves 5-hydroxymethyl-2-deoxyuridine-5-monophosphate (hmdUMP), preventing incorporation of the correspondent non-natural nucleotide into DNA. Recent findings have demonstrated that loss of DNPH1 could potentiate the sensitivity of PARP inhibitors in homologous recombination repair (HRR)-deficient cancers. We report the optimization of a non-nucleoside-based series of DNPH1 inhibitors. Starting from a weak compound 1 (binding affinity pIC50 4.7), we identified compound 38 as a very potent inhibitor of DNPH1 (pIC50 9.3) using DNPH1 X-ray structure-guided drug design. Compound 38 demonstrated target engagement of DNPH1 in the SUM149PT cell line (pIC50 7.2). Using this tool compound, we then report the in vitro pharmacology of a DNPH1 inhibitor in the BRCA1 mutant SUM149PT cell line.
What Do Oral Drugs Really Look Like? Dose Regimen, Pharmacokinetics, and Safety of Recently Approved Small-Molecule Oral Drugs
https://pubs.acs.org/doi/full/10.1021/acs.jmedchem.5c02863
Abstract
An analysis of dose, dose frequency, human pharmacokinetics, and potential drug–drug interactions (DDI) was performed on small-molecule oral drugs approved by the FDA from 2020 to 2024 (n = 104). Although most oral drugs are administered QD (67%), BID and TID regimens are also regularly approved (32%). First-in-class (FIC) drugs and drugs with Orphan Drug Designation (ODD) have a higher frequency of BID or TID administration compared to drugs without those designations (BID and TID = 50% for FIC drugs vs 19% for non-FIC; BID and TID = 41% for ODD vs 20% non-ODD). Most drugs are >95% plasma protein bound (58%), with a large fraction >99% bound (29%). Of these drugs, 22% have black box warnings and 42% list contraindications. An examination of DDI revealed the most frequent warning around CYP3A4 induction (60%). These findings will help medicinal chemists better understand and predict typical and nontypical profiles of oral drugs.
Discovery of CFT8634, a Potent, Selective, and Orally Bioavailable Heterobifunctional Degrader of BRD9
https://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.5c01317
Abstract
The chromatin factor bromodomain-containing protein 9 (BRD9) is a genetic dependency in SMARCB1-perturbed or SMARCB1-null cancers including synovial sarcoma. In such cancers, the degradation of BRD9 is hypothesized to result in an anticancer effect. Here, we report the discovery and characterization of CFT8634, an orally bioavailable heterobifunctional degrader that mediates potent and selective proteasomal degradation of BRD9. Oral dosing of CFT8634 in preclinical mouse xenograft models led to dose-dependent BRD9 degradation and tumor growth inhibition. Based on its promising preclinical profile, CFT8634 was advanced into a Phase 1 study in patients with SMARCB1-perturbed and -null tumors. CFT8634 demonstrated dose-dependent increases in human exposure with robust pharmacodynamic response but only modest efficacy outcomes in late-line patients. Further, the advancement of CFT8634 as a monotherapy was inhibited by the emergence of cardiac toxicities. Nevertheless, this first study of an orally bioavailable BRD9 degrader recapitulates preclinical pharmacokinetic and pharmacodynamic observations in a clinical trial setting.
Fragment-to-Lead Medicinal Chemistry Publications in 2024: A Tenth Annual Perspective
https://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.5c02894
Abstract
Fragment-based drug discovery (FBDD) has led to dozens of clinical compounds, including eight approved drugs. For the past decade, we have published an annual review of successful fragment-to-lead (F2L) medicinal chemistry programs. This Perspective marks the tenth in the series. We analyze the 18 F2L case studies from 2024 and put them in the context of the larger set of 233 examples dating back to 2015. We hope that the lessons herein will both inform and inspire researchers to discover the next generation of drugs.
