Structure-Guided Inhibitor Design Expands the Scope of Analog-Sensitive Kinase Technology

作者：Zhang Chao; Lopez Michael S; Dar Arvin C; LaDow Eva; Finkbeiner Steven; Yun Cai Hong; Eck Michael J; Shokat Kevan M^*

来源：ACS Chemical Biology, 2013, 8(9): 1931-1938.

DOI：10.1021/cb400376p

Engineered analog-sensitive (AS) protein kinases have emerged as powerful tools for dissecting phospho-signaling pathways, for elucidating the cellular function of individual kinases, and for deciphering unanticipated effects of clinical therapeutics. A crucial and necessary feature of this technology is a bioorthogonal small molecule that is innocuous toward native cellular systems but potently inhibits the engineered kinase. In order to generalize this method, we sought a molecule capable of targeting divergent AS-kinases. Here we employ X-ray crystallography and medicinal chemistry to unravel the mechanism of current inhibitors and use these insights to design the most potent, selective, and general AS-kinase inhibitors reported to date. We use large-scale kinase inhibitor profiling to characterize the selectivity of these molecules as well as examine the consequences of potential off-target effects in chemical genetic experiments. The molecules reported here will serve as powerful tools in efforts to extend AS-kinase technology to the entire kinome and the principles discovered may help in the design of other engineered enzyme/ligand pairs.

• 出版日期2013-9