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.

Automated summary

Due to the limited targets for drug development, triple-negative breast cancer (TNBC) is considered a challenging disease for chemotherapy. In this study, a set of novel electrophilic warheads was used to search for potential targets for TNBC in chemical proteomics studies. These warheads were found to modify not only highly nucleophilic residues but also weakly nucleophilic residues. Cys12 of Kirsten rat sarcoma (KRASG12C) was successfully labeled by cyclopropenone and cyclopropeniminium ions. Preliminary results showed moderate inhibitory activity against TNBC cells with these electrophile-based probes, and FABP5 was identified as a potential target for TNBC through further functional validation experiments.