The study, published in RSC Medicinal Chemistry describes the development of a novel oxidative phosphorylation (OXPHOS) inhibitor capable of reducing oxygen consumption in tumour cells. By lowering cellular oxygen demand, the compound increases oxygen availability within tumours, alleviating hypoxia and potentially increasing tumour sensitivity to radiotherapy.
The research was led by Professor Geoff Higgins from the Department of Oncology in collaboration with Professor Christopher Schofield from the Department of Chemistry.
Hypoxia is a common feature of solid tumours. It arises because rapidly growing tumours develop abnormal and chaotic blood vessel networks, creating poorly oxygenated regions within the cancer. These hypoxic areas are strongly associated with poor treatment outcomes, particularly in radiotherapy. One of the main ways in which radiotherapy exerts its cancer killing effects is by generating DNA strand breaks, which are much harder for cancer cells to repair under hypoxic conditions.
Although tumour hypoxia has been recognised as a major barrier to effective treatment for decades, attempts to overcome it have faced significant challenges.
“Despite over 50 years of research to target tumour hypoxia, there has been no major translation into improved clinical practice”, said Professor Geoff Higgins, study lead. “Most strategies have focused on increasing oxygen delivery or directly targeting hypoxic cells, but these approaches have been limited by toxicity, poor delivery into hypoxic regions, or insufficient efficacy.”
Instead, the researchers explored a different strategy: oxygen redistribution.
Targeting oxygen consumption
The team focused on inhibiting oxidative phosphorylation (OXPHOS). By suppressing OXPHOS activity, tumour cells consume less oxygen, increasing local oxygen availability within the tumour microenvironment.
As OXPHOS is a fundamental process across all cells, developing effective inhibitors requires a careful balance between potency, efficacy and safety. Previous candidates have either caused unacceptable toxicity or lacked sufficient potency and tumour uptake.
In this study, researchers screened over 1,600 FDA-approved small molecules for their ability to reduce oxygen consumption rates (OCR) in cancer cells. Fenofibrate, a prodrug widely used to treat hyperlipidemia, was identified as a promising candidate.
Dose-response studies showed that fenofibrate reduced OCR across all tested cell lines while having minimal impact on cell viability. In several tumour spheroid models, fenofibrate abolished hypoxia at clinically relevant concentrations, with hypoxia returning after drug washout, confirming that the effect depended on fenofibrate exposure.
Professor Geoff Higgins said:
“Fenofibrate is a known weak inhibitor of complex I of the electron transport chain. Our investigations showed that the decrease in oxygen consumption induced by fenofibrate corresponded to a decrease in hypoxia in a 3D in vitro cancer model, without influencing cytotoxicity. This made it a good starting point for developing safe and effective hypoxic modifiers.”
© Holt-Martyn, et al. 2026. Reproduced from RSC Medicinal Chemistry, [Structure-guided optimisation of fenofibrate-derived oxidative phosphorylation inhibitors to modify tumour hypoxia], CC BY 3.0 (https://creativecommons.org/licenses/by/3.0/).
Developing a more potent compound
Building on these findings, the researchers optimised the structure of fenofibrate to improve its potency as an OXPHOS inhibitor. Using structure-activity relationship studies, the team systematically modified four distinct regions of the fenofibrate molecule. The aim was to improve OCR reduction while preventing ester hydrolysis, a process that can reduce drug stability and efficacy. After testing numerous structural modifications, those found to be most effective were combined to create a new generation of compounds with improved potency and favourable safety characteristics.
Among these, a compound known as IOX7 emerged as the lead candidate, demonstrating improved potency for OXPHOS inhibition, a superior solubility profile, and lack of in vitro cytotoxicity at effective doses, compared to fenofibrate. A priority patent has been filed as development moves towards in vivo testing.
Professor Christopher Schofield said:
“The novel compounds developed in our work appear to have a suitable potency for OXPHOS inhibition in cells and can successfully eliminate hypoxia in 3D models without inducing cytotoxicity, demonstrating their potential as non-toxic and effective hypoxia modifiers for in vivo studies.”
IOX7 will serve as the foundation for the development of further optimised compounds, with the ultimate aim of developing a clinically useful hypoxia-modifying agent to improve radiotherapy outcomes for patients with cancer.
‘Structure-guided optimisation of fenofibrate-derived oxidative phosphorylation inhibitors to modify tumour hypoxia' was published in RSC Medicinal Chemistry on 28th April 2026.