1160934-81-5Relevant articles and documents
Hybrid compound design to overcome the gatekeeper T338M mutation in cSrc
Getlik, Matth?us,Grütter, Christian,Simard, Jeffrey R.,Klüter, Sabine,Rabiller, Matthias,Rode, Haridas B.,Robubi, Armin,Rauh, Daniel
supporting information; experimental part, p. 3915 - 3926 (2009/12/28)
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.
