PMID- 35709396 OWN - NLM STAT- MEDLINE DCOM- 20220715 LR - 20220726 IS - 1520-4804 (Electronic) IS - 0022-2623 (Linking) VI - 65 IP - 13 DP - 2022 Jul 14 TI - Discovery of Potent and Selective Receptor-Interacting Serine/Threonine Protein Kinase 2 (RIPK2) Inhibitors for the Treatment of Inflammatory Bowel Diseases (IBDs). PG - 9312-9327 LID - 10.1021/acs.jmedchem.2c00604 [doi] AB - Receptor-interacting serine/threonine protein kinase 2 (RIPK2) has been demonstrated to be a promising target for treating inflammatory diseases. Herein, we describe the discovery and optimization of a series of RIPK2 inhibitors derived from an FLT3 inhibitor, CHMFL-FLT3-165. Compound 10w was identified to possess an IC(50) value of 0.6 nM for RIPK2 and greater than 50,000-fold selectivity over its family homologous kinase RIPK1 (IC(50) > 30 muM). It exhibited high kinase selectivity and inhibited RIPK2 to prevent NOD-induced cytokine production following muramyl dipeptide (MDP) stimulation. In an acute colitis model, compound 10w exerted better therapeutic effects than the JAK inhibitor filgotinib and the RIPK2 inhibitor WEHI-345. These robust results of in vitro and in vivo pharmacodynamic experiments demonstrate that RIPK2 as a therapeutic target shows potential abilities for the treatment of inflammatory bowel diseases. FAU - Yuan, Xue AU - Yuan X AD - Laboratory of Natural and Targeted Small Molecule Drugs, State Key Laboratory of Biotherapy and Cancer Center and Collaborative Innovation Center of Biotherapy, West China Hospital of Sichuan University, Chengdu 610041, China. FAU - Chen, Yong AU - Chen Y AD - Laboratory of Natural and Targeted Small Molecule Drugs, State Key Laboratory of Biotherapy and Cancer Center and Collaborative Innovation Center of Biotherapy, West China Hospital of Sichuan University, Chengdu 610041, China. FAU - Tang, Minghai AU - Tang M AD - Laboratory of Natural and Targeted Small Molecule Drugs, State Key Laboratory of Biotherapy and Cancer Center and Collaborative Innovation Center of Biotherapy, West China Hospital of Sichuan University, Chengdu 610041, China. FAU - Wei, Yuhan AU - Wei Y AD - Laboratory of Natural and Targeted Small Molecule Drugs, State Key Laboratory of Biotherapy and Cancer Center and Collaborative Innovation Center of Biotherapy, West China Hospital of Sichuan University, Chengdu 610041, China. FAU - Shi, Mingsong AU - Shi M AD - Laboratory of Natural and Targeted Small Molecule Drugs, State Key Laboratory of Biotherapy and Cancer Center and Collaborative Innovation Center of Biotherapy, West China Hospital of Sichuan University, Chengdu 610041, China. FAU - Yang, Yingxue AU - Yang Y AD - Laboratory of Natural and Targeted Small Molecule Drugs, State Key Laboratory of Biotherapy and Cancer Center and Collaborative Innovation Center of Biotherapy, West China Hospital of Sichuan University, Chengdu 610041, China. FAU - Zhou, Yanting AU - Zhou Y AD - Laboratory of Natural and Targeted Small Molecule Drugs, State Key Laboratory of Biotherapy and Cancer Center and Collaborative Innovation Center of Biotherapy, West China Hospital of Sichuan University, Chengdu 610041, China. FAU - Yang, Tao AU - Yang T AD - Laboratory of Natural and Targeted Small Molecule Drugs, State Key Laboratory of Biotherapy and Cancer Center and Collaborative Innovation Center of Biotherapy, West China Hospital of Sichuan University, Chengdu 610041, China. FAU - Liu, Jiang AU - Liu J AD - Laboratory of Natural and Targeted Small Molecule Drugs, State Key Laboratory of Biotherapy and Cancer Center and Collaborative Innovation Center of Biotherapy, West China Hospital of Sichuan University, Chengdu 610041, China. FAU - Liu, Kongjun AU - Liu K AD - Laboratory of Natural and Targeted Small Molecule Drugs, State Key Laboratory of Biotherapy and Cancer Center and Collaborative Innovation Center of Biotherapy, West China Hospital of Sichuan University, Chengdu 610041, China. FAU - Deng, Dexin AU - Deng D AD - Laboratory of Natural and Targeted Small Molecule Drugs, State Key Laboratory of Biotherapy and Cancer Center and Collaborative Innovation Center of Biotherapy, West China Hospital of Sichuan University, Chengdu 610041, China. FAU - Zhang, Chufeng AU - Zhang C AD - Laboratory of Natural and Targeted Small Molecule Drugs, State Key Laboratory of Biotherapy and Cancer Center and Collaborative Innovation Center of Biotherapy, West China Hospital of Sichuan University, Chengdu 610041, China. FAU - Chen, Lijuan AU - Chen L AUID- ORCID: 0000-0002-8076-163X AD - Laboratory of Natural and Targeted Small Molecule Drugs, State Key Laboratory of Biotherapy and Cancer Center and Collaborative Innovation Center of Biotherapy, West China Hospital of Sichuan University, Chengdu 610041, China. AD - Chengdu Zenitar Biomedical Technology Co., Ltd., Chengdu 610041, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20220616 PL - United States TA - J Med Chem JT - Journal of medicinal chemistry JID - 9716531 RN - 0 (Protein Kinase Inhibitors) RN - 2ZD004190S (Threonine) RN - 452VLY9402 (Serine) RN - 53678-77-6 (Acetylmuramyl-Alanyl-Isoglutamine) RN - EC 2.7.11.1 (RIPK2 protein, human) RN - EC 2.7.11.1 (Receptor-Interacting Protein Serine-Threonine Kinase 2) RN - EC 2.7.11.1 (Receptor-Interacting Protein Serine-Threonine Kinases) SB - IM MH - Acetylmuramyl-Alanyl-Isoglutamine/metabolism MH - Humans MH - *Inflammatory Bowel Diseases/drug therapy MH - Protein Kinase Inhibitors/chemistry/pharmacology/therapeutic use MH - *Receptor-Interacting Protein Serine-Threonine Kinase 2 MH - Receptor-Interacting Protein Serine-Threonine Kinases MH - Serine MH - Threonine EDAT- 2022/06/17 06:00 MHDA- 2022/07/16 06:00 CRDT- 2022/06/16 15:52 PHST- 2022/06/17 06:00 [pubmed] PHST- 2022/07/16 06:00 [medline] PHST- 2022/06/16 15:52 [entrez] AID - 10.1021/acs.jmedchem.2c00604 [doi] PST - ppublish SO - J Med Chem. 2022 Jul 14;65(13):9312-9327. doi: 10.1021/acs.jmedchem.2c00604. Epub 2022 Jun 16.