AI Article Synopsis

  • Covalent kinase inhibitors, particularly selective 2-aminopyrimidine-based FGFR4 inhibitors, show promising clinical benefits and target specific enzymes involved in cancer.
  • A study explored various cysteine-targeting warheads, identifying α-fluoro acrylamide, vinylsulfonamide, and acetaldehyde amine as effective for developing selective inhibitors with significant suppression of FGFR4 activity.
  • X-ray crystal structure and MALDI-TOF analyses revealed that one compound binds irreversibly while another binds reversibly to FGFR4, providing valuable insights for future design of selective FGFR4 inhibitors.

Article Abstract

Covalent kinase inhibitors are rapidly emerging as a class of therapeutics with clinical benefits. Herein we report a series of selective 2-aminopyrimidine-based fibroblast growth factor receptor 4 (FGFR4) inhibitors exploring different types of cysteine-targeting warheads. The structure-activity relationship study revealed that the chemically tuned warheads α-fluoro acrylamide, vinylsulfonamide, and acetaldehyde amine were suitable as covalent warheads for the design of selective FGFR4 inhibitors. Compounds , , and selectively suppressed FGFR4 enzymatic activity with IC values of 53 ± 18, 45 ± 11, and 16 ± 4 nM, respectively, while sparing FGFR1/2/3. X-ray crystal structure and MALDI-TOF studies demonstrated that compound bearing the α-fluoro acrylamide binds to FGFR4 with an irreversible binding mode, whereas compound with an acetaldehyde amine binds to FGFR4 with a reversible covalent mode. and might provide some fundamental structural information for the rational design of new selective FGFR4 inhibitors.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8040253PMC
http://dx.doi.org/10.1021/acsmedchemlett.1c00052DOI Listing

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