Novel Electrophilic Warhead Targeting a Triple-Negative Breast Cancer Driver in Live Cells Revealed by "Inverse Drug Discovery"

  • J Med Chem. 2021 Nov 11;64(21):15582-15592. doi: 10.1021/acs.jmedchem.0c02024.
Youlong Fan  1 ,  Hongfei Si  1 ,  Zhang Zhang  1 ,  Liang Zhong  1 ,  Hongyan Sun  2 ,  Chengjun Zhu  1 ,  Zhibin Yin  3 ,  Huilin Li  3 ,  Guanghui Tang  4 ,  Shao Q Yao  4 ,  Pinghua Sun  1 ,  Zhi-Min Zhang  1 ,  Ke Ding  1 ,  Zhengqiu Li  1
Affiliations
  • 1. School of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China.
  • 2. Department of Chemistry, City University of Hong Kong, Hong Kong 999077, China.
  • 3. School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
  • 4. Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore 117543, Singapore.
PMID: 34623802 DOI: 10.1021/acs.jmedchem.0c02024
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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