A Fast Method to Monitor Tyrosine Kinase Inhibitor Mechanisms

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.