Optimization of α-Fluoro, β-Heteroaryl Acrylamide Warheads for KRASG12C Active-State Inhibition

  • J Med Chem. 2026 Mar 12;69(5):5935-5943. doi: 10.1021/acs.jmedchem.5c03307.
Matthew L Condakes  1 ,  Rita L Civiello  1 ,  Brian L Venables  1 ,  Derek B Danahy  1 ,  Richard R Moore  1 ,  Srividya B Balachander  1 ,  Lisa Sinang Chourb  1 ,  Daniel P Downes  2 ,  Dieter M Drexler  1 ,  Liudmila Dzhekieva  2 ,  Miriam El-Samin  1 ,  Sirish Kaushik Lakkaraju  2 ,  Christopher Levins  2 ,  Matthew J Meyer  1 ,  Katherine Mosure  1 ,  Michael F Parker  1 ,  Jie Qi  1 ,  Jack L Sloane  1 ,  Matthew Soars  1 ,  Justin Stedman  1 ,  Nicolas Szapiel  2 ,  Rebecca L Thompson  1 ,  Yong-Jin Wu  1 ,  Zhuo Zhang  1 ,  Xiaoliang Zhuo  1 ,  Michelle L Stewart  1 ,  Joanne J Bronson  1
Affiliations
  • 1. Bristol Myers Squibb, 250 Water St., Cambridge, Massachusetts 02446, United States.
  • 2. Bristol Myers Squibb, Route 206 and Province Line Rd., Princeton, New Jersey 08540, United States.
PMID: 41770619 DOI: 10.1021/acs.jmedchem.5c03307
Abstract

We provide herein a detailed investigation of the warhead reactivity and pharmaceutical properties of a novel α-fluoro, β-heteroaryl acrylamide class of covalent warhead in the context of KRASG12C active-state inhibition. Unlike traditional unsubstituted acrylamide warheads, which undergo conjugate addition with cysteine at the β-position, these acrylamides react at the α-position in a vinylogous nucleophilic aromatic substitution (SNAr) transformation. Systematic examination of pyridine warhead substitutions and bioisosteric replacements elucidated a dependence of these warheads' reactivity on heterocycle basicity in addition to electrophilicity. In vitro characterization revealed the effects of heterocycle identity on cellular potency, free fraction, permeability, and efflux ratio. These lessons informed in vivo studies, culminating in the discovery of a lead molecule that showed low clearance across species and robust efficacy in a mouse xenograft model.

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