Dihydroorotate Dehydrogenase Inhibitors in Cancer and Viral Therapeutics

The enzyme dihydroorotate dehydrogenase (DHODH) occupies a pivotal position in the de novo synthesis of pyrimidine nucleotides, coupling mitochondrial respiratory function to nucleotide production. In rapidly proliferating neoplastic cells and in cells infected by certain viruses, the demand for pyrimidine pools increases dramatically. Inhibition of DHODH thus restricts nucleotide availability, leading to cell cycle arrest, induction of differentiation or apoptosis in cancer cells, and activation of innate antiviral responses in viral infections. A growing arsenal of selective DHODH inhibitors has been developed, some repurposed from autoimmune indications, others designed de novo for enhanced potency and bioavailability. These agents display broad therapeutic potential, ranging from targeted treatment of myeloid malignancies through p53 activation to broad-spectrum antiviral activity against respiratory RNA viruses including coronaviruses. Their global significance is underscored by recent pandemics and the persistent challenge of chemotherapy resistance, highlighting DHODH inhibition as a robust strategy for translational research and clinical application.

Research from Nature Portfolio

Recent studies have identified novel chiral tetrahydroindazole inhibitors that bind selectively to human DHODH, revealing a frequent structural motif in p53 activators. These compounds arrest tumour cells in S-phase, elevate p53 synthesis and, when combined with inhibitors of p53 degradation, synergistically enhance tumour cell killing. High-resolution crystal structures of the active enantiomers in complex with DHODH have elucidated key binding interactions, informing future design of more potent and selective inhibitors. In vivo experiments demonstrate that these agents reduce tumour growth without genotoxic stress, suggesting a promising therapeutic avenue for cancers retaining wild-type p53.

Dihydroorotate Dehydrogenase Inhibitors in Cancer and Viral Therapeutics publication trend

The graph below shows the total number of articles in dihydroorotate dehydrogenase inhibitors in cancer and viral therapeutics across all publications each year (not limited to Nature Index journals).

Technical terms

Dihydroorotate dehydrogenase (DHODH): Mitochondrial enzyme catalysing the fourth step in de novo pyrimidine biosynthesis.

De novo pyrimidine synthesis: Metabolic pathway that generates pyrimidine nucleotides from basic precursors rather than salvaging them.

p53: A tumour suppressor protein that regulates the cell cycle, DNA repair and apoptosis.

EC₅₀ (half-maximal effective concentration): Concentration of a drug that elicits 50 percent of its maximum biological response.

Innate immunity: The non-specific first line of defence in the immune system, mediated by host cells and soluble factors.

References

1. DHODH and cancer: promising prospects to be explored. Cancer & Metabolism (2021).
2. A DHODH inhibitor increases p53 synthesis and enhances tumor cell killing by p53 degradation blockage. Nature Communications (2018).
3. The novel dihydroorotate dehydrogenase (DHODH) inhibitor BAY 2402234 triggers differentiation and is effective in the treatment of myeloid malignancies. Leukemia (2019).
4. IMU-838, a Developmental DHODH Inhibitor in Phase II for Autoimmune Disease, Shows Anti-SARS-CoV-2 and Broad-Spectrum Antiviral Efficacy In Vitro. Viruses (2020).
5. Broad-spectrum inhibition of common respiratory RNA viruses by a pyrimidine synthesis inhibitor with involvement of the host antiviral response. Journal of General Virology (2017).
6. Inhibition of Pyrimidine Biosynthesis Pathway Suppresses Viral Growth through Innate Immunity. PLOS Pathogens (2013).