3g5d

Publication Abstract from PubMed

The emergence of drug resistance remains a fundamental challenge in the development of kinase inhibitors that are effective over long-term treatments. Allosteric inhibitors that bind to sites lying outside the highly conserved ATP pocket are thought to be more selective than ATP-competitive inhibitors and may circumvent some mechanisms of drug resistance. Crystal structures of type I and allosteric type III inhibitors in complex with the tyrosine kinase cSrc allowed us to employ principles of structure-based design to develop these scaffolds into potent type II kinase inhibitors. One of these compounds, 3c (RL46), disrupts FAK-mediated focal adhesions in cancer cells via direct inhibition of cSrc. Details gleaned from crystal structures revealed a key feature of a subset of these compounds, a surprising flexibility in the vicinity of the gatekeeper residue that allows these compounds to overcome a dasatinib-resistant gatekeeper mutation emerging in cSrc.

Hybrid compound design to overcome the gatekeeper T338M mutation in cSrc.,Getlik M, Grutter C, Simard JR, Kluter S, Rabiller M, Rode HB, Robubi A, Rauh D J Med Chem. 2009 Jul 9;52(13):3915-26. PMID:19462975^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.