PDF(Pubmed)
Abstract：
Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) functions as a key regulator in inflammation and cell death and is involved in mediating a variety of inflammatory or degenerative diseases. A number of allosteric RIPK1 inhibitors (RIPK1i) have been developed, and some of them have already advanced into clinical evaluation. Recently, selective RIPK1i that interact with both the allosteric pocket and the ATP-binding site of RIPK1 have started to emerge. Here, we report the rational development of a new series of type-II RIPK1i based on the rediscovery of a reported but mechanistically atypical RIPK3i. We also describe the structure-guided lead optimization of a potent, selective, and orally bioavailable RIPK1i, 62, which exhibits extraordinary efficacies in mouse models of acute or chronic inflammatory diseases. Collectively, 62 provides a useful tool for evaluating RIPK1 in animal disease models and a promising lead for further drug development.
摘要：
受体-丝氨酸/苏氨酸蛋白激酶1(RIPK1)在炎症和细胞死亡中起关键调节因子的作用,并参与介导多种炎症或退行性疾病。已经开发了许多变构RIPK1抑制剂(RIPK1i)，其中一些已经进入临床评估。最近,与RIPK1的变构口袋和ATP结合位点相互作用的选择性RIPK1i已经开始出现。这里,基于对已报道但机械上非典型的RIPK3i的重新发现，我们报告了一系列新的II型RIPK1i的合理开发。我们还描述了一种有效的结构引导引线优化，选择性,和口服生物利用度RIPK1i，62,其在急性或慢性炎性疾病的小鼠模型中表现出非凡的功效。总的来说，图62提供了用于在动物疾病模型中评估RIPK1的有用工具和用于进一步药物开发的有希望的线索。
