Development of first-in-class antagonists of the retinoid pathway as novel oral therapies for Type 2 Diabetes

点击翻译按钮获取中文摘要

Project Summary: The retinoid pathway is a central regulatory pathway in human biology that has been considered undruggable for the last 20 years. It is activated when dietary vitamin A is transported to target tissues, is oxidized to all-trans retinoic acid (atRA), and then binds the RARα/β/γ nuclear receptors. This binding results in transcriptional regulation that is best known to influence the differentiation state of various cells and tissues. In metabolic disorders, ALDH1a3 is a key enzyme responsible for the final synthetic step of the retinoid ligand, and has also been identified as one of the principal pancreatic β cell markers for Type 2 diabetes. Numerous studies have shown that ALDH1a3 protein levels or enzymatic activity is a specific marker for failing/dedifferentiated β cells that lose the ability to produce insulin in Type 2 diabetics. Whereas retinoid signaling has long been a pathway of interest in both rodent and human diabetes, published studies have not established whether or not retinoid signaling and thus ALDH1a3 are drivers of Type 2 diabetes. Our initial discovery work suggests that ALDH1a3 is a driver of the β cell dedifferentiation observed in Type 2 diabetes and thus may offer a target whose inhibition can offer durable treatment effects for diabetics. Discussions with stakeholders across the Type 2 Diabetes community have demonstrated considerable interest in disease-modifying therapies that restore pancreatic function as there is broad recognition that current therapies are limited in activity to controlling blood glucose levels and insulin sensitivity rather than affecting pancreatic health. Thus, to reverse the projected rise of Type 2 diabetics across the world, next generation drug combinations are needed that restore pancreatic β cells to their normal differentiation status. Utilizing proprietary chemistry platforms, Kayothera is the first group to have developed lead inhibitors against ALDH1a3 that show exceptional potency and specificity while avoiding the pharmacologic liabilities of other drug development programs in the retinoid pathway. Our therapies show strong potency in inhibiting the retinoid pathway (<5 nM cellular, a 200-fold improvement over published molecules), no off-target activity, high metabolic stability, excellent oral pharmacokinetic properties and promising in vivo toxicology. Here we propose to nominate an IND development candidate through dose-range finding studies and PD/efficacy models. The results of this research proposal will advance a first-in-class therapy toward clinical testing with the aim of restoring pancreatic health to millions of patients in need.