title: Structure-guided inhibitor design expands the scope of analog-sensitive kinase technology.
abstract: 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.
authors.affiliation: Howard Hughes Medical Institute and Department of Cellular & Molecular Pharmacology, University of California, San Francisco , San Francisco, California 94158, United States.
authors.forename: Chao
authors.initials: C
authors.lastname: Zhang
authors.forename: Michael S
authors.initials: MS
authors.lastname: Lopez
authors.forename: Arvin C
authors.initials: AC
authors.lastname: Dar
authors.forename: Eva
authors.initials: E
authors.lastname: Ladow
authors.forename: Steven
authors.initials: S
authors.lastname: Finkbeiner
authors.forename: Cai-Hong
authors.initials: CH
authors.lastname: Yun
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Eck
authors.forename: Kevan M
authors.initials: KM
authors.lastname: Shokat
mesh_terms: D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D011494:Protein Kinases / Q000737:chemistry / Q000378:metabolism
chemical_list: D047428:Protein Kinase Inhibitors; D011494:Protein Kinases