Structure-based development of potent and selective type-II kinase inhibitors of RIPK1.

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

Return

Structure-based development of potent and selective type-II kinase inhibitors of RIPK1.

Author: Ying QIN ¹ ; Dekang LI ¹ ; Chunting QI ¹ ; Huaijiang XIANG ¹ ; Huyan MENG ¹ ; Jingli LIU ¹ ; Shaoqing ZHOU ¹ ; Xinyu GONG ² ; Ying LI ² ; Guifang XU ¹ ; Rui ZU ¹ ; Hang XIE ³ ; Yechun XU ² ; Gang XU ⁴ ; Zheng ZHANG ⁴ ; Shi CHEN ⁵ ; Lifeng PAN ⁶ ; Ying LI ¹ ; Li TAN ¹
Author Information

1. Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201210, China.
2. University of Chinese Academy of Sciences, Beijing 100049, China.
3. School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.
4. Institute of Hepatology, National Clinical Research Center for Infectious Disease, Shenzhen Third People's Hospital, the Second Affiliated Hospital, School of Medicine, Southern University of Science and Technology, Shenzhen 518112, China.
5. Department of Burn and Plastic Surgery, Shenzhen Institute of Translational Medicine, Shenzhen University Medical School, Shenzhen Second People's Hospital, the First Affiliated Hospital of Shenzhen University, Shenzhen 518035, China.
6. State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China.
Publication Type:Journal Article
Keywords: Anti-inflammation; Lead optimization; Necroptosis; Preclinical drug discovery; RIPK1; Rational design; Structure‒activity relationship; Type-II kinase inhibitors
From: Acta Pharmaceutica Sinica B 2024;14(1):319-334
CountryChina
Language:English
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.