木桶
化学
神经鞘素
鸟苷酸激酶
钙调蛋白
蛋白激酶A
激酶
细胞生物学
生物化学
生物
酶
膜
遗传学
膜蛋白
受体
突触后电位
作者
Nadine Russ,Martin Schröder,Benedict‐Tilman Berger,Sebastian Mandel,Yagmur Aydogan,Sandy Mauer,Christian Pohl,David H. Drewry,A. Chaikuad,Susanne Müller,Stefan Knapp
标识
DOI:10.1021/acs.jmedchem.1c00845
摘要
CASK (Ca2+/calmodulin-dependent Ser/Thr kinase) is a member of the MAGUK (membrane-associated guanylate kinase) family that functions as neurexin kinases with roles implicated in neuronal synapses and trafficking. The lack of a canonical DFG motif, which is altered to GFG in CASK, led to the classification as a pseudokinase. However, functional studies revealed that CASK can still phosphorylate substrates in the absence of divalent metals. CASK dysfunction has been linked to many diseases, including colorectal cancer, Parkinson's disease, and X-linked mental retardation, suggesting CASK as a potential drug target. Here, we exploited structure-based design for the development of highly potent and selective CASK inhibitors based on 2,4-diaminopyrimidine-5-carboxamides targeting an unusual pocket created by the GFG motif. The presented inhibitor design offers a more general strategy for the development of pseudokinase ligands that harbor unusual sequence motifs. It also provides a first chemical probe for studying the biological roles of CASK.
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