Despite significant advances in cancer care and treatment, it continues to be the second largest cause of death for U.S. adults. Cancer actually comprises many different diseases, and even within a single patient cancer evolves over time. Thus, multiple approaches are required, ideally matched to each patient’s disease. Our approach stems from an appreciation that many cancer cells metabolize nutrients and generate energy in different ways than healthy cells. We are studying a family of proteins called pyruvate dehydrogenase kinases (PDHKs) that play an important role in controlling glucose metabolism and energy production. Specifically, these mitochondrial proteins regulate the pyruvate dehydrogenase complex and perform an important function in toggling cell metabolism between glycolysis and oxidative phosphorylation. The over-expression of members of the PDHK family is associated with poor outcomes in cancer patients and inhibition of PDHKs can inhibit tumor growth in preclinical models. Preliminary clinical data using a weak and non-specific PDHK inhibitor suggest that the same effect can be achieved in human patients. In our lab, we have used computational chemistry to identify several novel small molecule inhibitors of PDHKs. These compounds are now being synthetized in the lab and optimized for testing in models of cancer.
- Infectious Diseases
Many infectious diseases continue to threaten human health especially in less develop parts of the world. The COVID-19 pandemic is a sobering reminder of the potential of infectious agents such a bacteria and viruses to change in ways that make them more easily transmitted to and between humans, and more difficult to control. Our contribution to scientific efforts specifically targeted at new drugs for treating COVID, has been to prepare inhibitors of the SARS-CoV-2 ribosomal frameshift RNA pseudoknot. Inhibitors of this regulatory RNA motif exhibit antiviral activity. This project fits with our larger interest in small molecules that bind to RNA and exhibit interesting biological activities.
- Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
ME/CFS, also known as Systemic Exertion Intolerance Disease (SEID) and Chronic Fatigue and Immune Dysfunction Syndrome (CFIDS) is a poorly understood disease characterized by chronic and debilitating fatigue, post-exertional malaise, and pain. It is difficult to diagnose, heterogeneous in nature, with symptoms varying widely between patients, and there are no approved treatments in the U.S. or Europe. The cause of ME/CFS is not known, however many patients report the first onset of symptoms following an acute viral infection. Scientists studying ME/CFS have repeatedly identified mitochondrial dysfunction as one of the hallmarks of disease, although this has not yet led to the introduction of useful diagnostic tools or new treatments. We are interested in using the tools of medicinal chemistry to identify pharmacological tools and treatments to understand and tackle this devastating disease.