Cyclopropenone, Cyclopropeniminium Ion, and Cyclopropenethione as Novel Electrophilic Warheads for Potential Target Discovery of Triple-Negative Breast Cancer,Journal of Medicinal Chemistry

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Cyclopropenone, Cyclopropeniminium Ion, and Cyclopropenethione as Novel Electrophilic Warheads for Potential Target Discovery of Triple-Negative Breast Cancer
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2023-02-10 , DOI: 10.1021/acs.jmedchem.2c01889
Shumin Lv ₁ , Fang Xu ₁ , Youlong Fan ₁ , Ke Ding ₁ , Zhengqiu Li ₁

Affiliation

Because very few targets are currently available for drug development, triple-negative breast cancer (TNBC) has been defined as one of the most difficult diseases for chemotherapy. Herein, we describe a suite of novel electrophilic warheads, which we have used in chemical proteomics studies in a search for potential targets for TNBC. Binding site analysis revealed that these warheads can modify not only highly nucleophilic residues, including cysteine and lysine, but also weakly nucleophilic residues. Cys12 of Kirsten rat sarcoma (KRAS^G12C) was successfully labeled by cyclopropenone and the cyclopropeniminium ions. Moderate inhibitory activity against TNBC cells was achieved with these novel electrophile-based probes. Activity-based protein profiling reveals that these electrophiles can covalently label a series of essential protein targets, including ALDH2, LRPPRC, and FABP5 from MDA-MB-231 cells. Further functional validation experiments demonstrated that FABP5 might be a potential target for TNBC.

中文翻译：

环丙烯酮、环丙烯亚胺离子和环丙烯硫酮作为新型亲电弹头用于发现三阴性乳腺癌的潜在靶点

由于目前可用于药物开发的靶点非常少，三阴性乳腺癌（TNBC）被定义为最难化疗的疾病之一。在此，我们描述了一套新型亲电子弹头，我们已将其用于化学蛋白质组学研究，以寻找 TNBC 的潜在靶标。结合位点分析表明，这些弹头不仅可以修饰高度亲核的残基，包括半胱氨酸和赖氨酸，还可以修饰弱亲核的残基。Kirsten 大鼠肉瘤的 Cys12 (KRAS ^G12C) 被环丙烯酮和环丙烯亚胺离子成功标记。这些新型的基于亲电试剂的探针实现了对 TNBC 细胞的适度抑制活性。基于活性的蛋白质分析表明，这些亲电子试剂可以共价标记一系列必需的蛋白质靶标，包括来自 MDA-MB-231 细胞的 ALDH2、LRPPRC 和 FABP5。进一步的功能验证实验表明 FABP5 可能是 TNBC 的潜在目标。

更新日期：2023-02-10

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