2. Academic Validation
  3. Novel Covalent Probe Selectively Targeting Glutathione Peroxidase 4 In Vivo: Potential Applications in Pancreatic Cancer Therapy

Novel Covalent Probe Selectively Targeting Glutathione Peroxidase 4 In Vivo: Potential Applications in Pancreatic Cancer Therapy

  • J Med Chem. 2024 Feb 8;67(3):1872-1887. doi: 10.1021/acs.jmedchem.3c01608.
Zifeng Tang 1 2 3,  Jie Li 1 2 3,  Lijie Peng 1 2 3,  Fang Xu 1 2 3,  Yi Tan 1 2 3,  Xiaoqiang He 1 2 3,  Chengjun Zhu 1 2 3,  Zhi-Min Zhang 1 2 3,  Zhang Zhang 1 2 3,  Pinghua Sun 1 2 3,  Ke Ding 1 2 3,  Zhengqiu Li 1 2 4 3
Affiliations

Affiliations

  • 1 State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China.
  • 2 International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development (MOE), Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China.
  • 3 School of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China.
  • 4 MOE Key Laboratory of Tumor Molecular Biology, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China.
PMID: 38265413 DOI: 10.1021/acs.jmedchem.3c01608
Abstract

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.

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