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Development of a Highly Selective c-Src Kinase Inhibitor

2012; American Chemical Society; Volume: 7; Issue: 8 Linguagem: Inglês

10.1021/cb300172e

1554-8937

Kristoffer Brandvold, Michael E. Steffey, Christel C. Fox, Matthew B. Soellner,

Quinazolinone synthesis and applications

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.