Novel Electrophilic Warhead Targeting a Triple-Negative Breast Cancer Driver in Live Cells Revealed by “Inverse Drug Discovery”

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.