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Selective Covalent Targeting of Pyruvate Kinase M2 Using Arsenous Warheads

文献类型：期刊论文

作者Wang, Jingyao5,6; Zhou, Shaoqing5,6; Cheng, Yan6; Cheng, Lin3,4; Qin, Ying5,6; Zhang, Zhenfeng3,4; Bi, Aiwei2,5; Xiang, Huaijiang5,6; He, Xinheng3,4; Tian, Xiaoxu1
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2023-02-23
卷号66期号:4页码:2608-2621
DOI10.1021/acs.jmedchem.2c01563
文献子类Article
英文摘要There is growing interest in covalent targeted inhibitors in drug discovery against previously undruggable sites and targets. These molecules typically feature an electrophilic warhead that reacts with nucleophilic groups of protein residues, most notably the thiol group of cysteines. One main challenge in the field is to develop versatile utilizable warheads. Here, we characterize the unique features of novel arsenous warheads for reaction with thiol species in a reversible manner and further demonstrate that organoarsenic probes can be chemically tuned toward specific molecular targets by developing selective and potent inhibitors of pyruvate kinase M2 (PKM2). We show that compound 24 is a covalent and allosteric inhibitor of PKM2 and its orally bioavailable prodrug 25 exerts efficacious inhibition of PKM2-dependent tumor growth in vitro and in vivo. Our results introduce 25 and its derivatives as useful pharmacological tools and provide a general road map for targeting the protein cysteinome using arsenous warheads.
WOS关键词SHIKONIN ; INHIBITORS ; MOLECULES ; DISCOVERY ; APOPTOSIS ; DYNAMICS
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000927040000001
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/309714]  
专题新药研究国家重点实验室
通讯作者Li, Ying; Zhuang, Guanglei; Tan, Li
作者单位1.Chinese Acad Sci, Shanghai Adv Res Inst, Zhangjiang Lab, Natl Facil Prot Sci Shanghai, Shanghai 201210, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China;
3.Shanghai Jiao Tong Univ, Ren Ji Hosp, Shanghai Key Lab Gynecol Oncol, Sch Med, Shanghai 200240, Peoples R China;
4.Shanghai Jiao Tong Univ, Ren Ji Hosp, Shanghai Canc Inst, State Key Lab Oncogenes & Related Genes,Sch Med, Shanghai 200240, Peoples R China;
5.Univ Chinese Acad Sci, Beijing 100049, Peoples R China;
6.Chinese Acad Sci, Shanghai Inst Organ Chem, Interdisciplinary Res Ctr Biol & Chem, Shanghai 201210, Peoples R China;
推荐引用方式
GB/T 7714		 Wang, Jingyao,Zhou, Shaoqing,Cheng, Yan,et al. Selective Covalent Targeting of Pyruvate Kinase M2 Using Arsenous Warheads[J]. JOURNAL OF MEDICINAL CHEMISTRY,2023,66(4):2608-2621.
APA Wang, Jingyao.,Zhou, Shaoqing.,Cheng, Yan.,Cheng, Lin.,Qin, Ying.,...&Tan, Li.(2023).Selective Covalent Targeting of Pyruvate Kinase M2 Using Arsenous Warheads.JOURNAL OF MEDICINAL CHEMISTRY,66(4),2608-2621.
MLA Wang, Jingyao,et al."Selective Covalent Targeting of Pyruvate Kinase M2 Using Arsenous Warheads".JOURNAL OF MEDICINAL CHEMISTRY 66.4(2023):2608-2621.

入库方式： OAI收割

来源：上海药物研究所

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