Irreversible Inhibitors of c-Src Kinase That Target a Nonconserved Cysteine.

Authors: Kwarcinski FE, Fox CC, Steffey ME, Soellner MB
Publisher/Year: ACS Chem Biol. 2012 Nov 16;7(11):1910-7. Epub 2012 Sep 5.
Pub Med ID/Journal ID: PMID:22928736


We have developed the first irreversible inhibitors of wild-type c-Src kinase. We demonstrate that our irreversible inhibitors display improved potency and selectivity relative to that of their reversible counterparts. Our strategy involves modifying a promiscuous kinase inhibitor with an electrophile to generate covalent inhibitors of c-Src. We applied this methodology to two inhibitor scaffolds that exhibit increased cellular efficacy when rendered irreversible. In addition, we have demonstrated the utility of irreversible inhibitors in studying the conformation of an important loop in kinases that can control inhibitor selectivity and cause drug resistance. Together, we have developed a general and robust framework for generating selective irreversible inhibitors from reversible, promiscuous inhibitor scaffolds.