Shi Kunyu, Zhang Jifa, Zhou Enda, Wang Jiaxing, Wang Yuxi
Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, Joint Research Institution of Altitude Health, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041 Sichuan, China.
Precision Medicine Key Laboratory of Sichuan Province & Precision Medicine Research Center, West China Hospital, Sichuan University, Chengdu, 610041 Sichuan, China.
J Med Chem. 2022 Nov 24;65(22):14971-14999. doi: 10.1021/acs.jmedchem.2c01518. Epub 2022 Nov 8.
As a serine/threonine protein kinase, receptor-interacting protein 1 (RIP1) plays an important role in regulating the pathways in programmed cell death. Multifaceted human diseases (e.g., autoimmune diseases, inflammatory diseases, neurodegenerative diseases, and tumors) are closely related to RIP1 kinase. Therefore, small-molecule RIP1 inhibitors with precise targeting and good penetrability have recently been used in potentially therapeutic methods, attracting extensive researcher interest. GSK2982772, developed by GlaxoSmithKline (GSK), became the world's first RIP1 inhibitor approved for clinical research in 2014. Nine clinical trials assessing GSK2982772 have been performed. The most recent direction in RIP1 inhibitor development has been focused on RIP1 small-molecule inhibitors with higher potency, selectivity, and metabolic stability. In this Perspective, considering the structure, biological functions, and disease relevance of RIP1, we summarize the recent research progress in RIP1 small-molecule inhibitor development based on different binding modalities and discuss prospective strategies for designing additional RIP1 therapeutic agents.
作为一种丝氨酸/苏氨酸蛋白激酶，受体相互作用蛋白1（RIP1）在调节程序性细胞死亡途径中发挥着重要作用。多种人类疾病（如自身免疫性疾病、炎症性疾病、神经退行性疾病和肿瘤）都与RIP1激酶密切相关。因此，具有精确靶向性和良好渗透性的小分子RIP1抑制剂最近被用于潜在的治疗方法中，引起了研究人员的广泛关注。葛兰素史克公司（GSK）研发的GSK2982772在2014年成为全球首个获批用于临床研究的RIP1抑制剂。目前已经开展了9项评估GSK2982772的临床试验。RIP1抑制剂开发的最新方向集中在具有更高效力、选择性和代谢稳定性的RIP1小分子抑制剂上。在这篇综述中，我们结合RIP1的结构、生物学功能及其与疾病的相关性，基于不同的结合模式总结了RIP1小分子抑制剂开发的最新研究进展，并讨论了设计更多RIP1治疗药物的前瞻性策略。
