Novel BDK Inhibitors to Treat Cardiometabolic Diseases
Abstract
Background: When people are overweight and diabetic with high blood sugar, as a consequence of metabolic disorders, they will have higher risks of developing heart disease than the general population. Heart diseases with these phenotypes are distinct from regular heart failure and cannot be effectively treated by traditional therapies targeting high blood pressure or blood volume reduction. To compound the issue, obesity and diabetes incidences are still increasing in the US. Military personnel, Veterans and their family members, perhaps due to their unique stressful lifestyle and working environment, have a 20% higher frequency of obesity than the general population. This situation is especially severe for Veterans who suffer from post-traumatic stress disorder (PTSD), according to recent government studies. Therefore, there is an urgent need to combine metabolic disorders and heart disease as one disease, based on their shared defects in metabolic processes. Indeed, the Fiscal Year 2019 Peer Reviewed Medical Research Program enlists two topic areas, Cardiomyopathy and Diabetes, with direct relevance to the above pathophysiological conditions. Key Scientific Discoveries: In the past, most of our scientific research focused on sugars and fats as they are perceived to be the major problems in diabetes and obesity. Recently, we used powerful analytical tools to measure gene expression and metabolic profiles in an unbiased way from individuals and animals with obesity/diabetes and heart failure. Surprisingly, we found the most significant changes were not only related to sugar or fat, but also involved a special group of amino acids, called branched-chain amino acids (BCAAs). BCAAs cannot be made from our body and can only be obtained from food sources. Our body uses BCAAs not only as nutrients, but also as signals to control other activities such as growth. However, under obesity/diabetes or heart failure conditions, the sensing and regulation of BCAAs is defective. This leads to the accumulation of harmful metabolites from their degradation, which causes insulin insensitivity and heart failure. This new knowledge was validated in both human populations and animal models of diseases. The advance fundamentally changed our current thinking of the underlying causes for heart diseases associated with diabetes and obesity. Therapeutic Opportunities: From our previous studies, we know that a regulatory enzyme, called BDK, is responsible for shutting down the BCAA degradation pathway in diabetes and heart failure. Based on knowledge in the structure and function of this enzyme, Dr. Chuang’s team developed a drug to inhibit BDK. In parallel, Dr. Wang and his team reported that this inhibitor exerts potent effects to reverse diabetes and prevent heart failure in animal models. These exciting new findings demonstrated, for the first time, a new method for treating cardiometabolic disease with BDK inhibitors. To realize this new therapeutic potential, we need to optimize the drug to improve drug potency, drug safety, and drug ability in order that clinical trials can be initiated. That is the main goal of this proposal. Central Hypothesis and Research Objective: BDK activity is not only an emerging major contributor to the pathogenesis of cardiometabolic disease but also a novel therapeutic target with significant efficacy. The main objective is to bring this new concept to the clinic. Research Strategy: Specific Aim 1: Develop a new generation of BDK inhibitors with improved potency through structure-based design and high-throughput screening. Specific Aim 2: Optimize lead BDK inhibitors identified from Aim 1 through Investigative New Drug (IND)-enabling analyses including toxicology, potency, route, dosage of administration, and pharmacokinetic studies. Specific Aim 3: Validate the therapeutic efficacy of the new BDK inhibitors in preclinical animal models of cardiometabolic diseases. Impact:
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010592
Entities
People
- Yibin Wang
Organizations
- United States Army
- University of California, Los Angeles