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Small-Molecule Receptor-Interacting Protein 1 (RIP1) Inhibitors as Therapeutic Agents for Multifaceted Diseases: Current Medicinal Chemistry Insights and Emerging Opportunities
Journal of Medicinal Chemistry ( IF 7.3 ) Pub Date : 2022-11-08 , DOI: 10.1021/acs.jmedchem.2c01518 Kunyu Shi 1 , Jifa Zhang 1, 2, 3 , Enda Zhou 4 , Jiaxing Wang 5 , Yuxi Wang 1, 2, 3
Journal of Medicinal Chemistry ( IF 7.3 ) Pub Date : 2022-11-08 , DOI: 10.1021/acs.jmedchem.2c01518 Kunyu Shi 1 , Jifa Zhang 1, 2, 3 , Enda Zhou 4 , Jiaxing Wang 5 , Yuxi Wang 1, 2, 3
Affiliation
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.
中文翻译:
小分子受体相互作用蛋白 1 (RIP1) 抑制剂作为多方面疾病的治疗剂:当前的药物化学见解和新兴机遇
作为丝氨酸/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的通路中起着重要作用。多方面的人类疾病(例如,自身免疫性疾病、炎症性疾病、神经退行性疾病和肿瘤)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,引起了广泛的研究者兴趣。GSK2982772 由葛兰素史克公司(GSK)开发,于 2014 年成为全球首个获批用于临床研究的 RIP1 抑制剂。目前已开展了九项评估 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。
更新日期:2022-11-08
中文翻译:
小分子受体相互作用蛋白 1 (RIP1) 抑制剂作为多方面疾病的治疗剂:当前的药物化学见解和新兴机遇
作为丝氨酸/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的通路中起着重要作用。多方面的人类疾病(例如,自身免疫性疾病、炎症性疾病、神经退行性疾病和肿瘤)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,引起了广泛的研究者兴趣。GSK2982772 由葛兰素史克公司(GSK)开发,于 2014 年成为全球首个获批用于临床研究的 RIP1 抑制剂。目前已开展了九项评估 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。