Disease-modifying drugs for T2D through targeting the Unfolded Protein Response

Project Summary/Abstract Type 2 diabetes (T2D) is a chronic degenerative cell disease characterized by hyperglycemia due to progressive progressive loss of overworked pancreatic islet beta cells. Recent work from our laboratories has shown that hyperactivation of the unfolded protein response (UPR) to ER stress in beta cells due to upstream may be a critical early event in the development of T2D. We have developed and are refining novel small molecule pharmacological reagents that allow us to manipulate critical components of the UPR—called KIRAs that maintain desirable (adaptive) outputs of the UPR while quelling undesirable (maladaptive) outputs including insulin resistance in peripheral tissues, consequently leading to apoptosis and diabetes. We show that first generation versions of KIRAs we developed against a kinase/RNase target called IRE1α can efficaciously prevent and even reverse diabetes in leptin deficient ob/ob mice. Here, we plan a medicinal chemistry campaign using several strategies to optimize KIRAs on three scaffolds towards the clinic. In this collaborative grant we will capitalize on the complementary expertise of the investigators to optimize these KIRA lead molecules for potency, selectivity, drug-likeness (including oral bioavailability) and conduct critical proof-of-concept studies using reductionist chemical genetic systems, ob/ob and HFD-fed mice, and human islets, and perform key IND-enabling steps needed to advance these candidates further into the clinic for eventually treating human patients with T2D.