Generation of Monospecific Nanomolar Tyrosine Kinase Inhibitors via a Chemical Genetic Approach

• DOI: 10.1021/ja983267v
• Publication Date: 2002-07-26T05:47:03Z
• Authors: Anthony C. Bishop; Chi-yun Kung; Kavita Shah; Laurie Witucki; Kevan M. Shokat; Yi Liu
• Keywords: Tyrosine-protein kinase CSK

Selective protein kinase inhibitors are highly sought after as tools for studying cellular signal transduction cascades, yet few have been discovered due to the conserved fold of catalytic domains. Through a combination small molecule synthesis and mutagenesis, potent (IC50 = 1.5 nM) uniquely specific inhibitor (4-amino-1-tert-butyl-3-(1'-naphthyl)pyrazolo[3,4-d]pyrimidine) rationally engineered v-Src tyrosine (Ile338Gly v-Src) has identified. Both potency specificity this compound surpass those any known Src family inhibitors. The strongly inhibits in whole cells but does not inhibit phosphorylation that express only wild-type kinases. In addition, selectively disrupts transformation target v-Src. structural degeneracy active sites should allow same complementary inhibitor/protein design strategy be widely applicable across entire enzyme superfamily.