UB researchers participate in the development of an anticancer drug using a pioneering precision medicine strategy
Cancer therapies continue to face significant limitations, such as tumour heterogeneity and the high systemic toxicity of many conventional treatments, which damage healthy tissues and reduce patients’ quality of life. To address this challenge, researchers from the University of Barcelona (UB) are participating in a new public–private consortium led by the pharmaceutical company Medchemfarma, whose objective is to develop an innovative anticancer compound with action restricted to specific organs. The University of Santiago de Compostela (USC) is also part of this initiative.
The innovative therapeutic strategy is based on the design and development of new inhibitors of dihydroorotate dehydrogenase (DHODH), an enzyme closely associated with the progression of a wide range of cancer types, making it an attractive therapeutic target for the development of new anticancer drugs.
“This project represents a paradigm shift in precision oncology by targeting DHODH with organ-restricted inhibitors, a strategy that is currently absent from existing anticancer drug development pipelines. With this approach, systemic toxicity would be minimised, and survival and quality of life could be improved for patients with aggressive cancers,” explains Sandra Pérez Torras, professor in the Department of Biochemistry and Molecular Biomedicine at the Faculty of Biology and leader of the UB research team involved in the project.
DHODH inhibitors developed to date have proven to be excessively toxic at effective doses, limiting their clinical potential. To overcome this issue, the new consortium will develop a precision medicine strategy based on the antedrug (or soft drug) paradigm. These are pharmacologically active compounds designed to act in the target organ and to be rapidly metabolised into inactive and excretable forms once they reach systemic circulation, thereby reducing side effects. “By restricting activity to target tissues, the new compounds could overcome the toxicity barriers associated with this class of drugs, enabling safer DHODH inhibition in solid tumours,” adds the researcher.
Dual-target strategy to prevent treatment resistance
In addition, the project will evaluate the potential synergistic effects resulting from the simultaneous inhibition of DHODH and the ENT1 transporter, which is involved in nucleoside uptake—molecules that are essential for cellular function.
The combined blockade of both targets aims to prevent tumour cells from compensating for DHODH inhibition by salvaging nucleosides from their environment, a common mechanism of resistance to treatment. “This combined strategy could enhance the patient’s immune system response by addressing two of the main mechanisms of tumour immune evasion,” the researcher explains.
Proven expertise in drug design and development
The collaboration between the pharmaceutical company Medchemfarma, the University of Barcelona and the University of Santiago de Compostela adds value thanks to their complementary expertise across all stages of the drug discovery and early development process, from molecular design to preclinical validation.
In an initial phase, the research team will focus on rational in silico (computational) design and the synthesis of new compounds, which will be protected by patent. Based on previously known DHODH inhibitors with demonstrated antitumour efficacy, optimised compounds will be developed to restrict their therapeutic action to target tissues and to ensure their subsequent rapid systemic inactivation.
In a second phase, the most promising molecules will undergo an exhaustive process of biological and pharmacological characterisation, combining in vitro and in vivo studies to evaluate their efficacy, selectivity and safety profile.
Finally, the project will conclude with the selection of a candidate with the potential to advance to the preclinical phase. If the expected objectives are achieved, this molecule could be positioned for a future phase I clinical trial as an immunotherapy for cancer patients.
The project, entitled “Discovery and early development of new DHODH enzyme inhibitors with organ-restricted activity for cancer treatment (DHODH-INHIB)”, will run for three years and has the reference CPP2024-011376. The University of Barcelona has received €333,941.60 in funding under the 2024 call for public–private collaboration projects, funded by the Ministry of Science, Innovation and Universities, the State Research Agency and the ERDF funds.