A Fast Method to Monitor Tyrosine Kinase Inhibitor Mechanisms

J Med Chem. 2024 Nov 28;67(22):20571-20579. doi: 10.1021/acs.jmedchem.4c02042. Epub 2024 Nov 8.

Abstract

Methionine residues within the kinase domain of Src serve as unique NMR probes capable of distinguishing between distinct conformational states of full-length Src, including alternative drug-inhibited forms. This approach offers a rapid method to differentiate between various inhibition mechanisms at any stage of drug development, eliminating the need to resolve the structure of Src-drug complexes. Using selectively 13C-methyl-enriched methionine, spectra can be acquired in under an hour, while natural abundance spectra with comparable information are achievable within a few hours.

MeSH terms

  • Humans
  • Magnetic Resonance Spectroscopy
  • Methionine / chemistry
  • Methionine / metabolism
  • Protein Kinase Inhibitors* / chemistry
  • Protein Kinase Inhibitors* / pharmacology
  • Tyrosine Kinase Inhibitors
  • src-Family Kinases / antagonists & inhibitors
  • src-Family Kinases / chemistry
  • src-Family Kinases / metabolism

Substances

  • Protein Kinase Inhibitors
  • src-Family Kinases
  • Methionine
  • Tyrosine Kinase Inhibitors