School of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China.
Department of Chemistry, City University of Hong Kong, Hong Kong 999077, China.
J Med Chem. 2021 Nov 11;64(21):15582-15592. doi: 10.1021/acs.jmedchem.0c02024. Epub 2021 Oct 8.
The "inverse drug discovery" strategy is a potent means of exploring the cellular targets of latent electrophiles not typically used in medicinal chemistry. Cyclopropenone, a powerful electrophile, is generally used in bio-orthogonal reactions mediated by triarylphosphine or in photo-triggered cycloaddition reactions. Here, we have studied, for the first time, the proteome reactivity of cyclopropenones in live cells and discovered that the cyclopropenone warhead can specifically and efficiently modify a triple-negative breast cancer driver, glutathione S-transferase pi-1 (GSTP1), by covalently binding at the catalytic active site. Further structure optimization and signaling pathway validation have led to the discovery of potent inhibitors of GSTP1.
“反向药物发现”策略是探索通常不用于药物化学的潜在亲电试剂的细胞靶标的有效手段。环丙烯酮是一种强亲电试剂，通常用于三芳基膦介导的生物正交反应或光触发环加成反应中。在这里，我们首次研究了环丙烯酮在活细胞中的蛋白质组反应性，发现环丙烯酮弹头可以通过在催化活性位点上共价结合，特异性和有效地修饰三阴性乳腺癌驱动蛋白谷胱甘肽 S-转移酶 pi-1 (GSTP1)。进一步的结构优化和信号通路验证导致发现了 GSTP1 的有效抑制剂。
