https://doi.org/10.1016/j.apsb.2023.10.021
This new article publication from Acta Pharmaceutica Sinica B, discusses the structure-based development of potent and selective type-II kinase inhibitors of RIPK1.
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.
The authors of this article report the rational development of a new series of type-II RIPK1i based on the rediscovery of a reported but mechanistically atypical RIPK3i. Also described is 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.
Keywords: RIPK1, Necroptosis, Type-II kinase inhibitors, Rational design, Lead optimization, Structure‒activity relationship, Anti-inflammation, Preclinical drug discovery
Graphical Abstract: available at https://ars.els-cdn.com/content/image/1-s2.0-S2211383523004215-ga1_lrg.jpg
Based on the rediscovery of a reported RIPK3 inhibitor (GSK’840) and structure-guided lead optimization, a potent, selective, and orally bioavailable type-II kinase inhibitor of RIPK1 (62) has been developed.
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The Journal of the Institute of Materia Medica, the Chinese Academy of Medical Sciences and the Chinese Pharmaceutical Association.
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CiteScore: 19.4
Impact Factor: 14.5
JIF without self-citation: 13.7
ISSN 2211-3835
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Ying Qin, Dekang Li, Chunting Qi, Huaijiang Xiang, Huyan Meng, Jingli Liu, Shaoqing Zhou, Xinyu Gong, Ying Li, Guifang Xu, Rui Zu, Hang Xie, Yechun Xu, Gang Xu, Zheng Zhang, Shi Chen, Lifeng Pan, Ying Li, Li Tan, Structure-based development of potent and selective type-II kinase inhibitors of RIPK1, Acta Pharmaceutica Sinica B, Volume 14, Issue 1, 2024, Pages 319-334, ISSN 2211-3835,
https://doi.org/10.1016/j.apsb.2023.10.021