Development of Highly Potent and Selective Covalent FGFR4 Inhibitors Based on SNAr Electrophiles

J Med Chem. 2024 Apr 25;67(8):6549-6569. doi: 10.1021/acs.jmedchem.3c02483. Epub 2024 Apr 11.

Abstract

Fibroblast growth factor receptor 4 (FGFR4) is thought to be a driver in several cancer types, most notably in hepatocellular carcinoma. One way to achieve high potency and isoform selectivity for FGFR4 is covalently targeting a rare cysteine (C552) in the hinge region of its kinase domain that is not present in other FGFR family members (FGFR1-3). Typically, this cysteine is addressed via classical acrylamide electrophiles. We demonstrate that noncanonical covalent "warheads" based on nucleophilic aromatic substitution (SNAr) chemistry can be employed in a rational manner to generate highly potent and (isoform-)selective FGFR4 inhibitors with a low intrinsic reactivity. Key compounds showed low to subnanomolar potency, efficient covalent inactivation kinetics, and excellent selectivity against the other FGFRs, the kinases with an equivalent cysteine, and a representative subset of the kinome. Moreover, these compounds achieved nanomolar potencies in cellular assays and demonstrated good microsomal stability, highlighting the potential of SNAr-based approaches in covalent inhibitor design.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Humans
  • Microsomes, Liver / metabolism
  • Protein Kinase Inhibitors* / chemical synthesis
  • Protein Kinase Inhibitors* / chemistry
  • Protein Kinase Inhibitors* / pharmacology
  • Receptor, Fibroblast Growth Factor, Type 4* / antagonists & inhibitors
  • Receptor, Fibroblast Growth Factor, Type 4* / metabolism
  • Structure-Activity Relationship

Substances

  • Receptor, Fibroblast Growth Factor, Type 4
  • Protein Kinase Inhibitors
  • FGFR4 protein, human