Development of a Highly Selective Ferroptosis Inducer Targeting GPX4 with 2-Ethynylthiazole-4-carboxamide as Electrophilic Warhead

  • J Med Chem. 2025 Feb 13;68(3):3309-3323. doi: 10.1021/acs.jmedchem.4c02530.
Sunkai Gu  1 ,  Guanyu Yang  1 ,  Hongyuan Bian  1 ,  Fan Yang  1 ,  Yajing Zhang  1 ,  Yanhong Huang  1 ,  Rui Su  1 ,  Huilian Zhang  1 ,  Xiuchun Zhao  1 ,  Jin Liu  1 ,  Shuheng Huang  1 ,  Ling Huang  1 ,  Benxin Hou  2 ,  Yong Rao  1 ,  Congjun Xu  1
Affiliations
  • 1. Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China.
  • 2. Department of General Surgery, Sanya Central Hospital (Hainan Third People's Hospital), Sanya 572000, China.
PMID: 39884957 DOI: 10.1021/acs.jmedchem.4c02530
Abstract

A highly selective Ferroptosis inducer with drug-like properties can significantly advance the research on inducing Ferroptosis for Anticancer treatment. We previously reported a highly active GPX4 inhibitor 26a, but its activity and stability need further improvement. In this work, a novel GPX4 inhibitor (R)-9i with more potent cytotoxicity (IC50 = 0.0003 μM against HT1080) and Ferroptosis selectivity (selectivity index = 24933) was gained via further electrophilic warhead screening and structure-based optimization. The cellular thermal shift assay (CETSA) indicated that (R)-9i could stabilize GPX4 with a Tm value of 6.2 °C. Furthermore, (R)-9i showed strong binding affinity against GPX4 (KD = 20.4 nM). More importantly, (R)-9i has more favorable pharmacokinetic properties than 26a, which endowed (R)-9i with potential in antitumor research and as a tool drug for further study of Ferroptosis. Associated with these, (R)-9i treatment significantly inhibited tumor growth in the xenograft tumor mouse model without detectable toxicity.

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