摘要
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.
基金
We thank Prof.Junying Yuan(IRCBC of CAS,Shanghai,China)and Dr.Jidong Zhu(Etern Therapeutics,Shanghai,China)for their generous help on this work,Dr.Sudan He(ISM of CAMS,Suzhou,China)for providing RIPK3-FKBP NIH/3T3 cells,and National Facility for Protein Science in Shanghai(China)for the help in animal studies.This work was supported by grants from the National Natural Science Foundation of China(Grants Nos.21837004,82151212,and 32170755)
the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB39050500,China)
Shanghai Municipal Science and Technology Major Project(Grant No.2019SHZDZX02,China).
