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ACS Chem Biol. 2018 Oct 19;13(10):2956-2965. doi: 10.1021/acschembio.8b00592. Epub 2018 Oct 9.

Type II Kinase Inhibitors Targeting Cys-Gatekeeper Kinases Display Orthogonality with Wild Type and Ala/Gly-Gatekeeper Kinases.

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Genome Damage and Stability Centre, School of Life Sciences , University of Sussex , Falmer, Brighton BN1 9RQ , U.K.
Howard Hughes Medical Institute and Department of Cellular and Molecular Pharmacology , University of California, San Francisco , 600 16th Street , San Francisco , California 94158-2280 , United States.
Department of Molecular and Cell Biology , University of Leicester , Henry Wellcome Building , Leicester LE1 9HN , U.K.
Department of Chemistry, School of Life Sciences , University of Sussex , Falmer, Brighton BN1 9QJ , U.K.
School of Molecular and Cellular Biology, Faculty of Biological Sciences , University of Leeds , Leeds LS2 9JT , U.K.


Analogue-sensitive (AS) kinases contain large to small mutations in the gatekeeper position rendering them susceptible to inhibition with bulky analogues 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 (analogue-sensitive "DFG-out" kinase inhibitors 2 and 6), that target the "DFG-out" conformation of 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.

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