Structure-guided optimisation of fenofibrate-derived oxidative phosphorylation inhibitors to modify tumour hypoxia

Journal article

Solid tumours frequently manifest regions of abnormally low levels of oxygen (hypoxia), which negatively impacts cancer treatment outcomes. This is particularly detrimental to radiotherapy which requires oxygen to exert maximal therapeutic effects. Tumour hypoxia can be abolished by reducing oxygen consumption rates (OCR) through inhibition of oxidative phosphorylation (OXPHOS), though to date no hypoxia modifying OXPHOS inhibitors have successfully translated into routine clinical practise. Here, we demonstrate that the well-tolerated, pro-drug fenofibrate, which has moderate OXPHOS inhibitory activity, can serve as a scaffold for OXPHOS inhibitor development. Structural modification of the four different regions of fenofibrate, that is its isopropyl-, dimethyl-, chloro-, and ketone-groups, improves potency for OCR inhibition whilst eliminating ester hydrolysis. The derivatives improve hypoxia alleviation in 3D spheroid models, without inducing cytotoxicity. Substrate-dependent oxygen consumption assays support complex I-specific inhibition as the mechanism of action. Structure activity relationship studies led to development of a lead compound (IOX7), which demonstrates improved potency for OXPHOS inhibition, a superior solubility profile, and lack of in vitro cytotoxicity at effective doses compared to fenofibrate. IOX7 has the potential for development as a clinically useful hypoxia-modifying OXPHOS inhibitor.

Authors: Holt-Martyn, JP; Machado, N; Coates, JTT; Puliyadi, R; Ashton, T

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Royal Society of Chemistry
• Journal: RSC Medicinal Chemistry
• Publication date: 2026-04-28
• Acceptance date: 2026-01-29
• DOI: 10.1039/d5md00742a
• EISSN: 2632-8682
• Language: English