Discovery of Highly Potent Nicotinamide Phosphoribosyltransferase Degraders for Efficient Treatment of Ovarian Cancer
文献类型：期刊论文
| 作者 | Bi, Kaijian1; Cheng, Junfei1; He, Shipeng2; Fang, Yuxin1; Huang, Min3 ; Sheng, Chunquan1; Dong, Guoqiang1
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| 刊名 | JOURNAL OF MEDICINAL CHEMISTRY
 |
| 出版日期 | 2022-12-23 |
| 页码 | 15 |
| ISSN号 | 0022-2623 |
| DOI | 10.1021/acs.jmedchem.2c01990 |
| 通讯作者 | Sheng, Chunquan(shengcq@smmu.edu.cn) ; Dong, Guoqiang(gdong@smmu.edu.cn) |
| 英文摘要 | Nicotinamide phosphoribosyltransferase (NAMPT) is identified as a promising target for cancer therapy. However, known NAMPT inhibitors are characterized by weak clinical efficacy and dose-dependent toxicity. There is an urgent need to develop new NAMPT intervention strategies. Using the proteolysis-targeting chimera (PROTAC) technology, we designed and synthesized a series of new von Hippel-Lindau (VHL)-recruiting NAMPT-targeting PROTACs. A highly potent NAMPT degrader (B3) was successfully identified, which displayed excellent degradation activity (DC50 < 0.17 nM, Dmax > 90%) and antiproliferative potency against A2780 cells (IC50 = 1.5 nM). PROTAC B3 induced NAMPT depletion in a concentration-and time-dependent manner through the ubiquitin-proteasome system. Particularly, PROTAC B3 achieved good plasma exposure levels via intravenous injection, gained potent tumor growth inhibition (TGI = 88.1%, 2 mu M/kg) in the xenograft model, and demonstrated good biosafety without undesired toxicities. This study provides a highly potent VHL-recruiting NAMPT degrader for the treatment of ovarian cancer. |
| WOS关键词 | NAMPT ; NAD(+) ; INHIBITORS ; PATHWAYS |
| 资助项目 | National Natural Science Foundation of China ; National Key Research and Development Program of China ; Shanghai Rising-Star Program ; [82273779] ; [82003567] ; [2022YFC3401500] ; [2020YFA0509100] ; [20QA1411700] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000904694500001 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/304183]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Sheng, Chunquan; Dong, Guoqiang |
| 作者单位 | 1.Second Mil Med Univ, Sch Pharm, Shanghai 200433, Peoples R China 2.Inst Translat Med, Shanghai 200444, Peoples R China 3.Chinese Acad Sci, Univ Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Bi, Kaijian,Cheng, Junfei,He, Shipeng,et al. Discovery of Highly Potent Nicotinamide Phosphoribosyltransferase Degraders for Efficient Treatment of Ovarian Cancer[J]. JOURNAL OF MEDICINAL CHEMISTRY,2022:15. |
| APA | Bi, Kaijian.,Cheng, Junfei.,He, Shipeng.,Fang, Yuxin.,Huang, Min.,...&Dong, Guoqiang.(2022).Discovery of Highly Potent Nicotinamide Phosphoribosyltransferase Degraders for Efficient Treatment of Ovarian Cancer.JOURNAL OF MEDICINAL CHEMISTRY,15. |
| MLA | Bi, Kaijian,et al."Discovery of Highly Potent Nicotinamide Phosphoribosyltransferase Degraders for Efficient Treatment of Ovarian Cancer".JOURNAL OF MEDICINAL CHEMISTRY (2022):15. |
入库方式： OAI收割
来源：上海药物研究所
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