蛋白激酶结构域
蛋白激酶A
生物
磷酸化
MAP激酶激酶激酶
细胞生物学
对接(动物)
丝裂原活化蛋白激酶激酶
作者
Cory A. Ocasio,Alexander A. Warkentin,Patrick J. McIntyre,Krister J. Barkovich,Clare Vesely,John Spencer,Kevan M. Shokat,Richard Bayliss
标识
DOI:10.1021/acschembio.8b00592
摘要
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 system...
科研通智能强力驱动
Strongly Powered by AbleSci AI