基于结构的ASK1抑制剂设计：作为心力衰竭潜在治疗药物
Structure-Based Design of ASK1 Inhibitors as Potential Agents for Heart Failure.
作者信息
Lanier Marion, Pickens Jason, Bigi Simone V, Bradshaw-Pierce Erica L, Chambers Alison, Cheruvallath Zacharia S, Cole Derek, Dougan Douglas R, Ermolieff Jacques, Gibson Tony, Halkowycz Petro, Hirokawa Aki, Ivetac Anthony, Miura Joanne, Nunez Evan, Sabat Mark, Tyhonas John, Wang Haixia, Wang Xiaolun, Swann Steve
机构信息
Departments of Medicinal Chemistry, Drug Metabolism Pharmacokinetics, Structural Biology, and Discovery Biology, Gastrointestinal Drug Discovery Unit, Takeda Pharmaceuticals , 10410 Science Center Drive, San Diego, California 92121, United States.
出版信息
ACS Med Chem Lett. 2017 Feb 8;8(3):316-320. doi: 10.1021/acsmedchemlett.6b00481. eCollection 2017 Mar 9.
Abstract
Apoptosis signal-regulating kinase 1 (ASK1/MAP3K) is a mitogen-activated protein kinase family member shown to contribute to acute ischemia/reperfusion injury. Using structure-based drug design, deconstruction, and reoptimization of a known ASK1 inhibitor, a lead compound was identified. This compound displayed robust MAP3K pathway inhibition and reduction of infarct size in an isolated perfused heart model of cardiac injury.
摘要
凋亡信号调节激酶1（ASK1/MAP3K）是一种丝裂原活化蛋白激酶家族成员，已被证明与急性缺血/再灌注损伤有关。通过基于结构的药物设计、解构和对已知ASK1抑制剂的重新优化，确定了一种先导化合物。在离体灌注心脏损伤模型中，该化合物表现出强大的MAP3K途径抑制作用并减小了梗死面积。
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