Title:Use of human Dihydroorotate Dehydrogenase (hDHODH) Inhibitors in Autoimmune Diseases and New Perspectives in Cancer Therapy
Volume: 13
Issue: 1
Author(s): Marco L. Lolli, Stefano Sainas, Agnese C. Pippione, Marta Giorgis, Donatella Boschi and Franco Dosio*
Affiliation:
- Department of Drug Science and Technology, University of Turin, via Pietro Giuria 9, 10125 Turin,Italy
Keywords:
Autoimmune diseases, brequinar, cancer, dihydroorotate dehydrogenase (DHODH), inhibitors, leflunomide, leukemia,
melanoma.
Abstract: Background: Human dihydroorotate dehydrogenase (hDHODH, EC 1.3.5.2), a flavindependent
mitochondrial enzyme involved in de novo pyrimidine biosynthesis, is a validated therapeutic
target for the treatment of autoimmune diseases, such as rheumatoid arthritis and multiple sclerosis.
However, human DHODH inhibitors have also been investigated as treatment for cancer, parasite
infections (i.e. malaria) and viruses as well as in the agrochemicals industry.
Objective: An overview of current knowledge of hDHODH inhibitors and their potential uses in diseases
where hDHODH is involved.
Method: This review focuses on recent advances in the development and application of hDHODH
inhibitors, specifically covering the patent field, starting from a brief description of enzyme topography
and of the strategies usually followed in designing its selective inhibitors.
Results: The most important and well-described novelty is the fact that the discovery, in the autumn of
2016, that hDHODH inhibitors are able to induce in vivo myeloid differentiation has led to the possibility
of developing novel hDHODH based treatments for Acute Myelogenous Leukemia (AML).
Conclusion: The review will describe a variety of specific inhibitor classes and conclude on recent
and future therapeutic perspectives for this target.
