Development of a Highly Selective c-Src Kinase Inhibitor

Authors: Kristoffer R. Brandvold, Michael E. Steffey, Christel C. Fox, and Matthew B. Soellner
Publisher/Year: ACS Chem Biol. 2012 Aug 17;7(8):1393-8. Epub 2012 Jun 4.
Pub Med ID/Journal ID: PMID:22594480


Generating highly selective probes to interrogate protein kinase function in biological studies remains a challenge, and new strategies are required. Herein, we describe the development of the first highly selective and cell-permeable inhibitor of c-Src, a key signaling kinase in cancer. Our strategy involves extension of traditional inhibitor design by appending functionality proposed to interact with the phosphate-binding loop of c-Src. Using our selective inhibitor, we demonstrate that selective inhibition is significantly more efficacious than pan-kinase inhibition in slowing the growth of cancer cells. We also show that inhibition of c-Abl kinase, an off-target of most c-Src inhibitors, promotes oncogenic cell growth.