LIBX‐A401: A Novel Selective Inhibitor of Acyl‐CoA Synthetase Long Chain Family Member 4 (ACSL4) and Its Binding Mode
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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.
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- Authors
- Mazhari Dorooee, D., Ravez, S., Vertommen, D., Renault, N., Papadopoulos, N., Marteau, R., Charnelle, E., Porte, K., Gobert, A., Hennuyer, N., Herinckx, G., Pautric, M., Jonneaux, A., Devedjian, J. C., Devos, D., Staels, B., Melnyk, P., Constantinescu, S. N., Frédérick, R., & El Bakali, J.
- Affiliations
- Medicinal Chemistry Research Group (CMFA) Louvain Drug Research Institute (LDRI) Université Catholique de Louvain 73 Avenue Mounier, B1.73.10 Brussels 1200 Belgium
- Inserm (FR)
- de Duve Institute (BE)
- Ludwig Cancer Research (BE)
- UCLouvain (BE)
- Laboratoire COBRA (FR)
- MASSPROT Platform de Duve Institute Université Catholique de Louvain Brussels Belgium
- Univ. Lille, Inserm CHU Lille UMR‐S‐U1172 – LilNCog – Lille Neuroscience & Cognition Lille F‐59000 France
- ORCID
- Venue
- Angewandte Chemie
- Publisher
- Wiley
- Published
- 2025-03-18
- Volume
- 137
- Issue
- 19
- ISSN
- 0044-8249 (ISSN-L)
- 1521-3757
- OpenAlex
- W4408333243
- Cited by
- 3
- References
- 48
- Citations by year
- 2026: 1 · 2025: 2
- FWCI
- 1.98
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Angewandte Chemie (publishedVersion, cc-by-nc)
- ChemRxiv (acceptedVersion, cc-by-nc-nd)
- Funders
- Fondation contre le Cancer (Ref: 3758)
- Région Hauts-de-France (Start‐AIRR FerInh4Park)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Physical Sciences › Chemistry › Organic Chemistry › Ferrocene Chemistry and Applications
- Keywords
- ACSL4, rosiglitazone, ferroptosis, cancer, fatty acid binding sites, hydrogen-deuterium exchange, photoaffinity labeling, molecular dynamics, inhibitor binding mode, lipid metabolism
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