LIBX‐A401: A Novel Selective Inhibitor of Acyl‐CoA Synthetase Long Chain Family Member 4 (ACSL4) and Its Binding Mode
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.
Authors
- Bart Staels (ORCID: https://orcid.org/0000-0002-3784-1503)
- Patricia Melnyk (ORCID: https://orcid.org/0000-0002-9555-3446)
- Karine Porte (ORCID: https://orcid.org/0000-0001-6132-5579)
- Nathalie Hennuyer (ORCID: https://orcid.org/0000-0003-0303-7258)
- Darius Mazhari Dorooee (ORCID: https://orcid.org/0000-0003-2276-8080)
- Gaëtan Herinckx (ORCID: https://orcid.org/0000-0002-3050-4459)
- Jamal El Bakali (ORCID: https://orcid.org/0000-0002-1470-0521)
- Aurélie Jonneaux
- Nicolas Papadopoulos (ORCID: https://orcid.org/0000-0001-7869-862X)
- Stefan N. Constantinescu (ORCID: https://orcid.org/0000-0002-8599-2699)
- Romain Marteau
- Nicolas Renault (ORCID: https://orcid.org/0000-0002-4859-1212)
- Didier Vertommen (ORCID: https://orcid.org/0000-0001-7648-8282)
- David Devos (ORCID: https://orcid.org/0000-0002-2417-799X)
- Séverine Ravez (ORCID: https://orcid.org/0000-0002-2394-8991)
- Raphaël Frédérick (ORCID: https://orcid.org/0000-0001-8119-1272)
- Jean‐Christophe Devedjian
- Alexandre Gobert
- Emeline Charnelle
- Maëla Pautric
Institutions
- Inserm (FR)
- Ludwig Cancer Research (BE)
- Université de Lille (FR)
- Institut Pasteur de Lille (FR)
- Centre Hospitalier Universitaire de Lille (FR)
- Ludwig Cancer Research (GB)
- de Duve Institute (BE)
- Lille Inflammation Research International Center (FR)
- Walloon Excellence in Lifesciences and Biotechnology (BE)
- Laboratoire COBRA (FR)
- Université de Rouen Normandie (FR)
- UCLouvain (BE)
Publication Details
- Journal
- Angewandte Chemie International Edition
- Published
- 2025-03-11
- DOI
- https://doi.org/10.1002/anie.202500518
- Citations
- 5
- Primary Topic
- Peroxisome Proliferator-Activated Receptors
- Type
- article
- Field-Weighted Citation Impact
- 4.03