Selective Covalent Targeting of Pyruvate Kinase M2 Using Arsenous Warheads,Journal of Medicinal Chemistry

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Selective Covalent Targeting of Pyruvate Kinase M2 Using Arsenous Warheads
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2023-02-01 , DOI: 10.1021/acs.jmedchem.2c01563
Jingyao Wang _{1,

2} , Shaoqing Zhou _{1,

2} , Yan Cheng ₁ , Lin Cheng _{3,

4} , Ying Qin _{1,

2} , Zhenfeng Zhang _{3,

4} , Aiwei Bi _{2,

5} , Huaijiang Xiang _{1,

2} , Xinheng He ₃ , Xiaoxu Tian ₆ , Wenbin Liu ₁ , Jian Zhang ₃ , Chao Peng ₆ , Zhengjiang Zhu ₁ , Min Huang ₅ , Ying Li ₁ , Guanglei Zhuang _{3,

4} , Li Tan ₁

Affiliation

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.

中文翻译：

使用砷弹头选择性共价靶向丙酮酸激酶 M2

在针对以前“不可药化”的位点和靶标的药物发现中，人们对共价靶向抑制剂的兴趣越来越大。这些分子通常具有与蛋白质残基的亲核基团反应的亲电子弹头，最显着的是半胱氨酸的硫醇基团。该领域的一项主要挑战是开发多功能的可利用弹头。在这里，我们描述了新型砷弹头以可逆方式与硫醇物种反应的独特特征，并进一步证明有机砷探针可以通过开发选择性和有效的丙酮酸激酶 M2 (PKM2) 抑制剂来化学调节特定分子靶标。我们表明化合物24是 PKM2 及其口服生物可利用前药25的共价变构抑制剂在体外和体内有效抑制 PKM2 依赖性肿瘤生长。我们的结果介绍了25及其衍生物作为有用的药理学工具，并提供了使用砷弹头靶向蛋白质半胱氨酸组的一般路线图。

更新日期：2023-02-01

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