2. Academic Validation
  3. Discovery of Potent Acyl-CoA Synthetase Long-Chain Family Member 4 (ACSL4) Inhibitors with Antiferroptotic Properties

Discovery of Potent Acyl-CoA Synthetase Long-Chain Family Member 4 (ACSL4) Inhibitors with Antiferroptotic Properties

  • J Med Chem. 2025 Aug 14;68(15):15766-15784. doi: 10.1021/acs.jmedchem.5c00739.
Emeline Charnelle 1,  Alexandre Gobert 1,  Romain Marteau 2,  Maëla Pautric 1 3,  Nicolas Renault 4,  Aurélie Jonneaux 1 3,  Darius Mazhari Dorooee 2,  Amélie Laversin 1,  Jean-Christophe Devedjian 1 3,  Patricia Melnyk 1,  Saïd Yous 1,  David Devos 1 3,  Raphaël Frédérick 2,  Séverine Ravez 1,  Jamal El Bakali 1
Affiliations

Affiliations

  • 1 Univ. Lille, Inserm, CHU Lille, UMR-S-U1172 - LilNCog - Lille Neuroscience & Cognition, Lille F-59000, France.
  • 2 Medicinal Chemistry Research Group (CMFA), Louvain Drug Research Institute (LDRI), Université Catholique de Louvain (UCLouvain), 73 avenue Mounier, Brussels B-1200, Belgium.
  • 3 Department of Medical Pharmacology, Expert Center of Parkinson's Disease, ALS and Neurogenetic, LICEND COEN Center Lille, Lille F-59000, France.
  • 4 INSERM, CHU Lille, U-1286 - INFINITE - Institute for Translational Research in Inflammation, Université de Lille, Lille F-59000, France.
PMID: 40682560 DOI: 10.1021/acs.jmedchem.5c00739
Abstract

Ferroptosis, an iron-dependent regulated cell death, is implicated in several diseases, including Cancer and neurodegeneration. While most Ferroptosis inhibitors act as radical-trapping Antioxidants, direct modulation of pro-ferroptotic Enzymes remains underexplored. Acyl-coenzyme A synthetase long-chain family member 4 (ACSL4), a key regulator of Ferroptosis, has emerged as a promising therapeutic target. Here, we report a fragment-based screening that identified a benzofuran hit (compound 8, IC50 = 33 μM), leading to the discovery of two selective ACSL4 inhibitors: compound 15b (LIBX-A402, IC50 = 0.33 μM) and compound 21 (LIBX-A403, IC50 = 0.049 μM). Compound 21 is the most potent ACSL4 inhibitor reported to date and shows no activity against ACSL3. Molecular modeling and mutagenesis support its binding in the ACSL4 fatty acid pocket. The strong antiferroptotic activity of both compounds in cells, together with confirmed target engagement for 21, underscores the relevance of ACSL4 as a target for Ferroptosis modulation.

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