posted on 2024-01-24, 15:38authored byZifeng Tang, Jie Li, Lijie Peng, Fang Xu, Yi Tan, Xiaoqiang He, Chengjun Zhu, Zhi-Min Zhang, Zhang Zhang, Pinghua Sun, Ke Ding, Zhengqiu Li
Glutathione
peroxidase 4 (GPX4) emerges as a promising target for
the treatment of therapy-resistant cancer through ferroptosis. Thus,
there is a broad interest in the development of GPX4 inhibitors. However,
a majority of reported GPX4 inhibitors utilize chloroacetamide as
a reactive electrophilic warhead, and the selectivity and pharmacokinetic
properties still need to be improved. Herein, we developed a compound
library based on a novel electrophilic warhead, the sulfonyl ynamide,
and executed phenotypic screening against pancreatic cancer cell lines.
Notably, one compound A16 exhibiting potent cell toxicity
was identified. Further chemical proteomics investigations have demonstrated
that A16 specifically targets GPX4 under both in situ
and in vivo conditions, inducing ferroptosis. Importantly, A16 exhibited superior selectivity and potency compared to reported
GPX4 inhibitors, ML210 and ML162. This provides
the structural diversity of tool probes for unraveling the fundamental
biology of GPX4 and exploring the therapeutic potential of pancreatic
cancer via ferroptosis induction.