AI Article Synopsis
- The "inverse drug discovery" strategy explores new cellular targets that aren't typically tapped into by traditional medicinal chemistry.
- Cyclopropenone, a strong electrophile, has been studied for its ability to react with proteins in live cells, specifically targeting the GSTP1 protein linked to triple-negative breast cancer.
- The research revealed that cyclopropenones can modify GSTP1 and led to the creation of effective inhibitors that counteract this cancer-driving protein.
Article 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.
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| http://dx.doi.org/10.1021/acs.jmedchem.0c02024 | DOI Listing |
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