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

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 (KRASG12C) 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.