Recent advances of human dihydroorotate dehydrogenase inhibitors for cancer therapy: Current development and future perspectives

Human dihydroorotate dehydrogenase (hDHODH) is a flavin-dependent enzyme catalyzing the fourth step of pyrimidine de novo biosynthesis. Since aberrant pyrimidine metabolism is closely related abnormal cell proliferation, hDHODH is believed to have an intimate linkage with cancers. For instance, hDHODH induces the abrogation of β-catenin degradation and cell proliferation in esophageal squamous cell carcinoma (ESCC). Thus, small molecular inhibitors targeting hDHODH has been considered as a promising strategy for cancer treatment. In recent years, in exploiting novel structural hDHODH inhibitors (hDHODHi), a candidate drug PTC299 has entered clinical trials for treating acute myelocytic leukemia (AML) and other tumors. This review discusses tumor-related research of hDHODH and highlights the structure-activity relationships of hDHODHi, providing insights into new drugs targeting hDHODH for antitumor clinical practice.