LIBX-A401: a novel selective inhibitor of acyl-coa synthetase long chain family member 4 (ACSL4) and its binding mode

Journal article

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: Mazhari Dorooee, D; Ravez, S; Vertommen, D; Renault, N; Papadopoulos, N

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Wiley
• Journal: Angewandte Chemie International Edition
• Volume: 64
• Issue: 19
• Article number: e202500518
• Place of publication: Germany
• Publication date: 2025-03-18
• Acceptance date: 2025-02-27
• DOI: 10.1002/anie.202500518
• EISSN: 1521-3773
• ISSN: 1433-7851
• Pmid: 40019446
• Language: English
• Keywords: ACSL4 inhibitors; ferroptosis; photoaffinity labeling; Parkinson’s disease; Hydrogen Deuterium Exchange (HDx) mass spectrometry