2. Academic Validation
  3. LIBX-A401: A Novel Selective Inhibitor of Acyl-CoA Synthetase Long Chain Family Member 4 (ACSL4) and Its Binding Mode

LIBX-A401: A Novel Selective Inhibitor of Acyl-CoA Synthetase Long Chain Family Member 4 (ACSL4) and Its Binding Mode

  • Angew Chem Int Ed Engl. 2025 May;64(19):e202500518. doi: 10.1002/anie.202500518.
Darius Mazhari Dorooee 1,  Séverine Ravez 2,  Didier Vertommen 3,  Nicolas Renault 4,  Nicolas Papadopoulos 5 6 7,  Romain Marteau 1,  Emeline Charnelle 2,  Karine Porte 1,  Alexandre Gobert 2,  Nathalie Hennuyer 8,  Gaetan Herinckx 3,  Maëla Pautric 2 9,  Aurélie Jonneaux 2 9,  Jean Christophe Devedjian 2 9,  David Devos 2 9,  Bart Staels 8,  Patricia Melnyk 2,  Stefan N Constantinescu 5 6 7 10,  Raphaël Frédérick 1,  Jamal El Bakali 2
Affiliations

Affiliations

  • 1 Medicinal Chemistry Research Group (CMFA), Louvain Drug Research Institute (LDRI), Université Catholique de Louvain, 73 Avenue Mounier, B1.73.10, Brussels, 1200, Belgium.
  • 2 Univ. Lille, Inserm, CHU Lille, UMR-S-U1172 - LilNCog - Lille Neuroscience & Cognition, Lille, F-59000, France.
  • 3 MASSPROT Platform, de Duve Institute, Université Catholique de Louvain, Brussels, Belgium.
  • 4 INSERM, CHU Lille, U-1286 - INFINITE - Institute for Translational Research in Inflammation, Université de Lille, Lille, F-59000, France.
  • 5 Ludwig Institute for Cancer Research, Brussels, Belgium.
  • 6 de Duve Institute, Université catholique de Louvain, Brussels, Belgium.
  • 7 WELBIO Department, WEL Research Institute, Wavre, Belgium.
  • 8 Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U-1011-EGID, Lille, F-59000, France.
  • 9 Department of Medical Pharmacology, Expert Center of Parkinson's Disease, ALS and neurogenetic, LICEND COEN Center Lille, Lille, F-59000, France.
  • 10 Ludwig Institute for Cancer Research, Nuffield Department of Medicine, Oxford University, Oxford, UK.
PMID: 40019446 DOI: 10.1002/anie.202500518
Abstract

Acyl-coenzyme A synthetase long-chain family member 4 (ACSL4), a pivotal enzyme in lipid metabolism, has emerged as a therapeutic target for ferroptosis-related conditions and Cancer. However, its reference inhibitor, rosiglitazone, has off-target activity on Peroxisome Proliferator-activated Receptor gamma (PPARγ), a key regulator of lipid homeostasis. Here, the discovery of LIBX-A401, a potent ACSL4 inhibitor derived from rosiglitazone devoid of PPARγ activity, is reported. Its binding to ACSL4 is ATP-dependent, stabilizing the C-terminal domain and altering the fatty acid gate region, as shown by Hydrogen-Deuterium Exchange Mass Spectrometry. Photoaffinity labeling identified A329 within the fatty acid binding site, while molecular dynamics and mutagenesis highlighted Q302 as critical for LIBX-A401 binding. LIBX-A401 exhibits anti-ferroptotic properties in cells, supported by target engagement. These findings establish LIBX-A401 as a valuable tool to study ACSL4 in Ferroptosis and Cancer, while its elucidated binding mode paves the way for the rational design of improved inhibitors.

Keywords

ACSL4 inhibitors; Ferroptosis; Hydrogen Deuterium Exchange (HDx) mass spectrometry; Parkinson's disease; Photoaffinity labeling.

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