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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Antineoplastic Agents / chemical synthesis
-
Antineoplastic Agents / chemistry
-
Antineoplastic Agents / pharmacology*
-
Cell Line, Tumor
-
Cell Proliferation / drug effects
-
Cell Survival / drug effects
-
Cyclopropanes / chemical synthesis
-
Cyclopropanes / chemistry
-
Cyclopropanes / pharmacology*
-
Dose-Response Relationship, Drug
-
Drug Discovery*
-
Drug Screening Assays, Antitumor
-
Enzyme Inhibitors / chemical synthesis
-
Enzyme Inhibitors / chemistry
-
Enzyme Inhibitors / pharmacology*
-
Glutathione S-Transferase pi / antagonists & inhibitors*
-
Glutathione S-Transferase pi / metabolism
-
Humans
-
Models, Molecular
-
Molecular Structure
-
Structure-Activity Relationship
-
Triple Negative Breast Neoplasms / drug therapy*
-
Triple Negative Breast Neoplasms / metabolism
-
Triple Negative Breast Neoplasms / pathology
Substances
-
Antineoplastic Agents
-
Cyclopropanes
-
Enzyme Inhibitors
-
cyclopropenone
-
GSTP1 protein, human
-
Glutathione S-Transferase pi