Novel Electrophilic Warhead Targeting a Triple-Negative Breast Cancer Driver in Live Cells Revealed by “Inverse Drug Discovery”
Youlong Fan, Hongfei Si, Zhang Zhang, Zhang Zhang, Liang Zhong, Hongyan Sun, Chengjun Zhu, Zhibin Yin, Huilin Li, Guanghui Tang, Shao Q. Yao, Pinghua Sun, Zhimin Zhang, Zhimin Zhang, Ke Ding, Zhengqiu Li
Abstract
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.