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Type II kinase inhibitors targeting Cys-gatekeeper kinases display orthogonality with wild type and Ala/Gly-gatekeeper kinases

DOI: 10.1021/acschembio.8b00592 DOI Help

Authors: Cory A. Ocasio (University of Sussex) , Alexander A. Warkentin (University of California, San Francisco) , Patrick J. Mcintyre (University of Leicester) , Krister J. Barkovich (University of California, San Francisco) , Clare Vesely (University of Sussex) , John Spencer (University of Sussex) , Kevan M. Shokat (University of California, San Francisco) , Richard Bayliss (University of Leeds)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Acs Chemical Biology

State: Published (Approved)
Published: September 2018

Abstract: Analog-sensitive (AS) kinases contain large to small mutations in the gatekeeper position rendering them susceptible to inhibition with bulky analogs of pyrazolopyrimidine-based Src kinase inhibitors (e.g. PP1). This ‘bump-hole’ method has been utilized for at least 85 of ~520 kinases, but many kinases are intolerant to this approach. To expand the scope of AS-kinase technology, we designed type II kinase inhibitors, ASDO2/6 (Analog-Sensitive ‘DFG-Out’ kinase inhibitors-2/6), that target the ‘DFG-out’ conformation of cysteine (Cys)-gatekeeper kinases with submicromolar potency. We validated this system in vitro against Greatwall kinase (GWL), Aurora-A kinase and Cyclin-dependent kinase-1 and in cells using M110C-GWL expressing mouse embryonic fibroblasts. These Cys-gatekeeper kinases were sensitive to ASDO2/6-inhibition, but not AS-kinase inhibitor 3MB-PP1 and vice versa. These compounds, with AS-kinase inhibitors, have the potential to inhibit multiple AS-kinases independently with applications in systems level and translational kinase research as well as the rational design of type II kinase inhibitors targeting endogenous kinases.

Subject Areas: Biology and Bio-materials, Chemistry


Instruments: I04-Macromolecular Crystallography