期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 64, 期 21, 页码 15582-15592出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.0c02024
关键词
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资金
- National Key R&D Program of China [2019YFC1711000]
- National Natural Science Foundation of China [22077051, 21877050, 82061128002]
- Science and Technology Program of Guangdong Province [2019B151502025]
- Synthetic Biology Research and Development Programme (SBP) of the National Research Foundation of Singapore [SBP-P4, SBP-P8]
The inverse drug discovery strategy utilizing cyclopropenone as a potent electrophile has led to the specific and efficient modification of the triple-negative breast cancer driver GSTP1 in live cells, resulting in the discovery of potential inhibitors through further optimization and pathway validation.
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 triplenegative 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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