Graduate School of Science, Osaka Prefecture University, Osaka 599-8531, Japan.
Whol Institute for Drug Discovery of the Nancy and Stephen Grand Israel National Center for Personalized Medicine, The Weizmann Institute of Science, Rehovot 7610001, Israel.
Bioorg Med Chem Lett. 2020 Nov 15;30(22):127546. doi: 10.1016/j.bmcl.2020.127546. Epub 2020 Sep 12.
Mitogen-activated protein kinase kinase 7 (MAP2K7) in the c-Jun N-terminal kinase signal cascade is an attractive drug target for a variety of diseases. The selectivity of MAP2K7 inhibitors against off-target kinases is a major barrier in drug development. We report a crystal structure of MAP2K7 complexed with a potent covalent inhibitor bearing an acrylamide moiety as an electrophile, which discloses a structural basis for producing selective and potent MAP2K7 inhibitors.
丝裂原活化蛋白激酶激酶 7（MAP2K7）位于 c-Jun N 端激酶信号级联中，是多种疾病的有吸引力的药物靶点。MAP2K7 抑制剂对非靶标激酶的选择性是药物开发的主要障碍。我们报告了一个 MAP2K7 与含有丙烯酰胺部分作为亲电体的有效共价抑制剂复合物的晶体结构，该结构揭示了产生选择性和有效 MAP2K7 抑制剂的结构基础。
