Cancer is the 2nd leading cause of death in the United States. In 2018, an estimated 1.7 million new cases of cancer will be diagnosed in the United States and over 600,000 people will die from the disease. Although many therapeutics exist to treat cancer of varying types, these therapies often fall short of adequately treating the disease and can have detrimental side effects. Our understanding of the genetic pathways regulating tumor cells continues to advance. With these advancements comes a better understanding of pathways regulating cell growth and proliferation of cancer cells. One specific enzymatic target, Dihydroorotate dehydrogenase (DHODH) was identified as a cell cycle regulator and implicated in cancer growth many years ago. An inhibitor of DHODH, brequinar, to treat cancer were first introduced nearly 60 years ago, however this therapeutic failed to effectively treat the disease. This new technology addresses the shortcomings of brequinar by using a structure-guided approach to better understand how DHODH regulates cell cycle targets. This approach resulted in the discovery of drastically improved DHODH inhibitors targeting specific residues shown to be important for DHODH activation. These novel compounds show promising results as new cancer therapeutics.
Keywords: DHODH, cancer, cell cycle inhibitor, acute myeloid leukemia, AML
Current stage: Research – in vitro
Publication: Madak JT, Cuthbertson CR, Miyata Y, et al. “Design, Synthesis, and Biological Evaluation of 4-Quinoline Carboxylic Acids as Inhibitors of Dihydroorotate Dehydrogenase. Journal of Medicinal Chemistry. 2018. 61(12);5163-5186.