Identification of a RANKL/TNF-α Dual-Inhibitor as a Potential Disease-Modifying Agent for the Treatment of Knee Osteoarthritis
文献类型：期刊论文
| 作者 | Shao, Zhengguang1,2,3; Wang, Tianqi4; Yan, Xueming4; Ning, Ruonan4; Xu, Xing4; He, Qian2 ; Zhang, Xiaofei2; Jiang, Min4; Yang, Chunhao1,2,3
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| 刊名 | JOURNAL OF MEDICINAL CHEMISTRY
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| 出版日期 | 2025-05-13 |
| 卷号 | 68期号:10页码:10216-10237 |
| ISSN号 | 0022-2623 |
| DOI | 10.1021/acs.jmedchem.5c00394 |
| 英文摘要 | Osteoarthritis (OA) is a multifactorial degenerative disease involved subchondral bone remodeling, cartilage destruction and synovium inflammation. While receptor activator of nuclear factor-kappa B ligand (RANKL), a tumor necrosis factor (TNF) superfamily protein, is the critical regulator in bone metabolism associated with subchondral bone resorption, TNF-alpha is also an important inflammatory factor involved in the OA inflammation and cartilage destruction. Based on previous compound Y1599, we identified a novel tetrahydro-beta-carboline derivative Y2641 with both RANKL and TNF-alpha inhibition in this study. Y2641 exhibited potent RANKL-induced osteoclastogenic inhibition (IC50 = 109.1 nM), and had anti-inflammatory and cartilage destruction inhibiting effects at 10 mu M with low cytotoxicity. SPR assays demonstrated the binding affinity of Y2641 to RANKL (K d = 3.984 mu M) and TNF-alpha (K d = 18.59 mu M). In vivo assay further revealed the disease-modifying effects of Y2641 in OA rats, establishing Y2641 as a promising lead compound for the development of disease-modifying osteoarthritis drugs. |
| WOS关键词 | DRUG ; PATHOGENESIS ; RANK ; EFFICACY ; SAFETY ; OPG |
| 资助项目 | National Natural Science Foundation of China[22277076] ; National Natural Science Foundation of China[22407087] ; National Natural Science Foundation of China[SKLDR-2023-KF-06] ; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:001487281000001 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/317917]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Zhang, Xiaofei; Jiang, Min; Yang, Chunhao |
| 作者单位 | 1.Lingang Lab, Shanghai 200021, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, State Key Lab Drug Res, Shanghai 201203, Peoples R China 3.ShanghaiTech Univ, Sch Phys Sci & Technol, Shanghai 201210, Peoples R China 4.Shanghai Jiao Tong Univ, Ruijin Hosp, Shanghai Inst Traumatol & Orthopaed, Sch Med,Dept Orthopaed,Shanghai Key Lab Prevent &, Shanghai 200025, Peoples R China |
| 推荐引用方式 GB/T 7714 | Shao, Zhengguang,Wang, Tianqi,Yan, Xueming,et al. Identification of a RANKL/TNF-α Dual-Inhibitor as a Potential Disease-Modifying Agent for the Treatment of Knee Osteoarthritis[J]. JOURNAL OF MEDICINAL CHEMISTRY,2025,68(10):10216-10237. |
| APA | Shao, Zhengguang.,Wang, Tianqi.,Yan, Xueming.,Ning, Ruonan.,Xu, Xing.,...&Yang, Chunhao.(2025).Identification of a RANKL/TNF-α Dual-Inhibitor as a Potential Disease-Modifying Agent for the Treatment of Knee Osteoarthritis.JOURNAL OF MEDICINAL CHEMISTRY,68(10),10216-10237. |
| MLA | Shao, Zhengguang,et al."Identification of a RANKL/TNF-α Dual-Inhibitor as a Potential Disease-Modifying Agent for the Treatment of Knee Osteoarthritis".JOURNAL OF MEDICINAL CHEMISTRY 68.10(2025):10216-10237. |
入库方式： OAI收割
来源：上海药物研究所
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