TY - JOUR
T1 - Novel Electrophilic Warhead Targeting a Triple-Negative Breast Cancer Driver in Live Cells Revealed by "inverse Drug Discovery"
AU - Fan, Youlong
AU - Si, Hongfei
AU - Zhang, Zhang
AU - Zhong, Liang
AU - Sun, Hongyan
AU - Zhu, Chengjun
AU - Yin, Zhibin
AU - Li, Huilin
AU - Tang, Guanghui
AU - Yao, Shao Q.
AU - Sun, Pinghua
AU - Zhang, Zhi-Min
AU - Ding, Ke
AU - Li, Zhengqiu
PY - 2021/11/11
Y1 - 2021/11/11
N2 - 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.
AB - 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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U2 - 10.1021/acs.jmedchem.0c02024
DO - 10.1021/acs.jmedchem.0c02024
M3 - RGC 21 - Publication in refereed journal
SN - 0022-2623
VL - 64
SP - 15582
EP - 15592
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 21
ER -
