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Discovery of Dual Function Agents That Exhibit Anticancer Activity via Catastrophic Nicotinamide Adenine Dinucleotide Depletion

文献类型：期刊论文

作者Fu, Yixian4,5; Huang, Yahui3; Zhou, Chenchen3; Li, Xinge2; Dong, Guoqiang3; Huang, Min1,4; Ding, Jian1,4,5; Sheng, Chunquan3
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2023-12-07
卷号66期号:24页码:16694-16703
ISSN号0022-2623
DOI10.1021/acs.jmedchem.3c01362
通讯作者Huang, Yahui(xiaohnhyh@163.com) ; Huang, Min(mhuang@simm.ac.cn) ; Ding, Jian(jding@simm.ac.cn) ; Sheng, Chunquan(shengcq@smmu.edu.cn)
英文摘要Nicotinamide adenine dinucleotide (NAD) is essentially involved in many biological processes of cancer cells, yet chemical intervention of NAD biosynthesis failed to obtain an optimal therapeutic benefit. We herein developed a new strategy to induce catastrophic NAD depletion by concurrently impairing NAD synthesis and promoting NAD consumption. We designed a series of new compounds that conjugate an inhibitor of nicotinamide phosphoribosyltransferase (NAMPT), a rate-limiting enzyme in the NAD salvage pathway, with a DNA-alkylating agent. Among them, compound 11b exhibited potent anticancer efficacy in cancer cell lines and mouse tumor models with intrinsic resistance to the parent compound FK866 or chlorambucil. Compound 11b caused catastrophic NAD depletion via a synergistic effect between the NAD salvage pathway blockade and DNA damage-triggered NAD consumption. Our findings suggest a new intervention strategy for causing catastrophic NAD depletion in cancer cells and provide basis for the development of new inhibitors targeting NAD metabolism.
WOS关键词PHOSPHORIBOSYLTRANSFERASE NAMPT ; INHIBITION ; CHS-828 ; TARGET ; CELLS ; FK866
资助项目National Key Research and Development Program of China[82030105] ; National Key Research and Development Program of China[82225046] ; National Key Research and Development Program of China[22277138] ; National Natural Science Foundation of China[2022YFC3401500] ; National Key Research and Development Program of China
WOS研究方向Pharmacology & Pharmacy
语种英语
出版者AMER CHEMICAL SOC
WOS记录号WOS:001134056200001
源URL[http://119.78.100.183/handle/2S10ELR8/308374]  
专题新药研究国家重点实验室
通讯作者Huang, Yahui; Huang, Min; Ding, Jian; Sheng, Chunquan
作者单位1.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai 264117, Peoples R China
2.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
3.Second Mil Med Univ, Naval Med Univ, Ctr Basic Res & Innovat Med & Pharm MOE, Sch Pharm, Shanghai 200433, Peoples R China
4.Chinese Acad Sci, State Key Lab Drug Res, Shanghai Inst Mat Med, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China
5.Nanchang Univ, Sch Pharm, Nanchang 330031, Peoples R China
推荐引用方式
GB/T 7714		 Fu, Yixian,Huang, Yahui,Zhou, Chenchen,et al. Discovery of Dual Function Agents That Exhibit Anticancer Activity via Catastrophic Nicotinamide Adenine Dinucleotide Depletion[J]. JOURNAL OF MEDICINAL CHEMISTRY,2023,66(24):16694-16703.
APA Fu, Yixian.,Huang, Yahui.,Zhou, Chenchen.,Li, Xinge.,Dong, Guoqiang.,...&Sheng, Chunquan.(2023).Discovery of Dual Function Agents That Exhibit Anticancer Activity via Catastrophic Nicotinamide Adenine Dinucleotide Depletion.JOURNAL OF MEDICINAL CHEMISTRY,66(24),16694-16703.
MLA Fu, Yixian,et al."Discovery of Dual Function Agents That Exhibit Anticancer Activity via Catastrophic Nicotinamide Adenine Dinucleotide Depletion".JOURNAL OF MEDICINAL CHEMISTRY 66.24(2023):16694-16703.

入库方式： OAI收割

来源：上海药物研究所

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