Thesis: Mohammed Moustapha Anwar

Director: Mari Angeles Juanes

Title: A Journey to the Discovery and Development of Next-Generation Inhibitors of Human Dihydroorotate Dehydrogenase (DHODH) for Cancer Therapy

Abstract: Human dihydroorotate dehydrogenase (DHODH) is the rate-limiting enzyme in pyrimidine de novo synthesis and represents a promising target for cancer therapy. Over the past four decades, all developed human DHODH inhibitors have targeted the same region: the hydrophobic tunnel. However, despite extensive efforts, no DHODH inhibitor has achieved approval for oncology indications. This thesis demonstrates that human DHODH can be targeted through an alternative mechanism using the natural small molecule NK-A 17E-233I, overcoming limitations associated with conventional inhibitors.
NK-A 17E-233I functions as a pure or partial competitive inhibitor of the natural substrate dihydroorotate (DHO), representing a distinct inhibitory mechanism compared to previously developed DHODH inhibitors. It exhibits cytotoxic activity in human cancer cell lines and patient-derived intestinal organoids, inducing DNA damage, S-phase arrest, and cell death. Unlike classical inhibitors, NK-A 17E-233I preserves mitochondrial respiration through complexes I and II while maintaining ATP-linked basal respiration. Through rational structural modification, this thesis further generated next-generation DHODH inhibitors, establishing a new direction for DHODH-targeted therapeutic development since the 1990s.