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DHODH

Targeting Leukemia by using innovative human dihydroorotate dehydrogenase inhibitors

Dihydroorotate dehydrogenase (DHODH) (EC 1.3.99.11) is a key enzyme in nucleotide synthesis. It catalyzes the fourth committed step in the biosynthesis of pyrimidines. In this step of the synthesis, (S)-dihydroorotate (DHO) is stereospecifically oxidized to orotate, while the prosthetic flavin (FMN) group is reduced. Inhibition of DHODH leads to reduced levels of essential pyrimidine precursors, among which is UMP, a critical component of RNA and DNA synthesis. Most organisms are able to both synthesize and salvage pyrimidine bases; however, rapidly proliferating human cells such as activated T-lymphocytes and cancer cells are dependent on nucleotide synthesis to meet their growth requirements. The suggestion that DHODH inhibitors may be used as antiproliferative agents in cancer therapy and in the treatment of rheumatoid arthritis, psoriasis, autoimmune diseases, bacterial, fungal and tropical parasitic infections is based on these findings.

Earlier, in a drug design project we solved the structure of human DHODH in complex with some inhibitors, among which was a brequinar analogue and a novel inhibitor (a fenamic acid derivative), as well as the first structure of the enzyme to be characterized without any bound inhibitor (Walse et al., 2008). 

Currently I am involved in a collaborative project targeting human DHODH for the treatment of Acute myeloid leukemia (AML). An international research team is involved in this project. The team includes experts in medicinal chemistry, compound design and synthesis (M. Lolli, Univ of Turin), biochemical in vitro profiling (Rosmarie Friemann, University of Gothenburg), biochemical profiling in AML cell lines (Giuseppe Saglio, Univ of Genua) and X-ray crystallography (Al-Karadaghi, Friemann). AML is a clinically devastating disease. It comprises many disparate genetic subtypes, but a shared distinctive feature is the arrest of leukemic myeloblasts at an immature and self-renewing stage of development. Recently, it was shown that inhibition of the metabolic enzyme involved in pyrimidine biosynthesis, dihydroorotate dehydrogenase (DHODH), induces differentiation of leukemic cells (Lewis et al., 2016; Sykes et al., 2016). DHODH inhibitors reduce leukemic cell burden, decrease the levels of leukemia-initiating cells, and improve survival.