From Hit to Lead: Discovery of Novel Selective RIPK1 Inhibitor with Pyridoimidazole Scaffold for the Treatment of Autoimmune Diseases through Phenotypic Screening and Structural Optimization
文献类型：期刊论文
| 作者 | Wan, Jihong5; Xiong, Xiao-Yu4,6; Geng, Zixiang2; Yuan, Benjun3; Ma, Youzhen1; Zhao, Yan5; Dorothy Wong, Zhi Ying5; Kang, Xinyi5; Fan, Rui5; Min, Delin5 |
| 刊名 | JOURNAL OF MEDICINAL CHEMISTRY
 |
| 出版日期 | 2026-02-12 |
| 卷号 | 69期号:3页码:3252-3288 |
| ISSN号 | 0022-2623 |
| DOI | 10.1021/acs.jmedchem.5c03145 |
| 英文摘要 | Autoimmune diseases remain challenging to treat due to the limitations of TNF alpha-targeted biologics and the inefficacy of small molecules directly targeting TNF alpha. RIPK1, a central mediator of TNF alpha-driven inflammation and necroptosis, offers a promising alternative therapeutic target. Using drug repurposing and phenotype-based high-content screening of 378 clinical-stage kinase inhibitors, TAK-117 (a PI3K alpha inhibitor) was identified as a RIPK1 hit compound with a novel pyridoimidazole scaffold. Guided by structure-based optimization and four iterative SAR cycles, WJH-C19 was developed, exhibiting >1000-fold increased RIPK1 potency (IC50 = 5.7 nM) and negligible PI3K alpha activity (IC50 > 10 mu M). Mechanistically, WJH-C19 suppressed the RIPK1/RIPK3/MLKL signaling axis, attenuating inflammatory responses. Oral administration of WJH-C19 achieved robust efficacy in DSS-induced colitis and CFA-induced arthritis models, with favorable pharmacokinetics and no observable toxicity. These results establish WJH-C19 as a potent lead and highlight the pyridoimidazole scaffold as a privileged chemotype for RIPK1-targeted drug discovery in autoimmune diseases. |
| WOS关键词 | KINASE INHIBITORS ; TNF-ALPHA ; NECROPTOSIS ; INFLAMMATION ; HOMEOSTASIS ; MLKL |
| 资助项目 | Xuzhou Medical University[D2023011] ; Quzhou Science and Technology Research and Development Program[2025K233] ; National Natural Science Foundation of China[82322076] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:001680264400001 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/322734]  |
| 专题 | 国家级研究中心_原创新药研究全国重点实验室 |
| 通讯作者 | Sun, Nannan; Zhao, Yongfang; Lin, Ze-Min; Tang, Mei-Lin |
| 作者单位 | 1.Xuzhou Med Univ, Sch Life Sci, 209 Tongshan Rd, Xuzhou 221004, Peoples R China 2.Shanghai Univ Tradit Chinese Med, Shuguang Hosp, Shis Ctr Orthoped & Traumatol, Inst Traumatol & Orthoped, Shanghai 201203, Peoples R China 3.Zhengzhou Univ, Sch Pharmaceut Sci, State Key Lab Antiviral Drugs, Coll Chem,Pingyuan Lab, Zhengzhou 450001, Peoples R China 4.Shanghai Univ Tradit Chinese Med, Guanghua Clin Med Coll, Shanghai 200052, Peoples R China 5.Fudan Univ, Human Phenome Inst, Shanghai Pudong Hosp,Pharmacophen Lab, Dept Nat Med,Sch Pharmaceut Sci, Shanghai 201203, Peoples R China 6.Chinese Acad Sci, Shanghai Inst Mat Med, Lab Immunopharmacol, State Key Lab Drug Res, Shanghai 201203, Peoples R China 7.Shanghai Univ Tradit Chinese Med, China Canada Ctr Res Digest Dis, State Key Lab Integrat & Innovat Class Formula & M, Inst Digest Dis,Longhua Hosp, Shanghai 200032, Peoples R China |
| 推荐引用方式 GB/T 7714 | Wan, Jihong,Xiong, Xiao-Yu,Geng, Zixiang,et al. From Hit to Lead: Discovery of Novel Selective RIPK1 Inhibitor with Pyridoimidazole Scaffold for the Treatment of Autoimmune Diseases through Phenotypic Screening and Structural Optimization[J]. JOURNAL OF MEDICINAL CHEMISTRY,2026,69(3):3252-3288. |
| APA | Wan, Jihong.,Xiong, Xiao-Yu.,Geng, Zixiang.,Yuan, Benjun.,Ma, Youzhen.,...&Tang, Mei-Lin.(2026).From Hit to Lead: Discovery of Novel Selective RIPK1 Inhibitor with Pyridoimidazole Scaffold for the Treatment of Autoimmune Diseases through Phenotypic Screening and Structural Optimization.JOURNAL OF MEDICINAL CHEMISTRY,69(3),3252-3288. |
| MLA | Wan, Jihong,et al."From Hit to Lead: Discovery of Novel Selective RIPK1 Inhibitor with Pyridoimidazole Scaffold for the Treatment of Autoimmune Diseases through Phenotypic Screening and Structural Optimization".JOURNAL OF MEDICINAL CHEMISTRY 69.3(2026):3252-3288. |
入库方式： OAI收割
来源：上海药物研究所
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