First in class substrate-selective Insulin Degrading Enzyme (IDE) inhibitors for treating Diabetes

First in class substrate-selective Insulin Degrading Enzyme (IDE) inhibitors for treating Diabetes. Professor David Liu and a multidisciplinary research team have recently discovered and optimized of a series of small molecules (<550 Da, IC50 = 1 nM) that inhibit the metalloprotease Insulin-Degrading Enzyme (IDE) with an unprecedented substrate-selective mechanism. IDE-mediated degradation of Insulin is completely abrogated, but the smaller substrate, Glucagon, is cleaved efficiently even at saturating concentration of inhibitor. An X-ray co-crystal structure of the ligand reveals binding to a distal pocket of IDE outside the catalytic site, which explains its remarkable affinity and specificity for IDE versus other metalloproteases, as well as its ability to competitively exclude Insulin from the IDE cavity without affecting the protease activity on other substrates, most importantly the counter-regulatory hormone, Glucagon. Recent studies using Type-2 Diabetes model mice have shown that acute IDE inhibition improves blood glucose clearance in oral glucose challenges, with concomitant elevation of insulin during experimental conditions that mimic a meal. These observations suggest an ideal therapeutic approach to selectively boost the endogenous insulin response to meals that is insufficient in pre- and mid-stage diabetic patients, allowing the body to regulate blood glucose levels and prevent the onset of disease symptoms.

The Liu group is an established leader in this field and validated IDE as a therapeutic target using the first agent to inhibit IDE-mediated insulin degradation in vivo (Maianti et al, Nature, 2014, 511, p94-8). Despite the fact that IDE has been extensively associated with Type-2 Diabetes and that IDE knock-out mice display very mild phenotypes, potent, selective, and physiologically active inhibitors have not been identified. Therefore, this is a unique opportunity to develop the first pharmaceutical agents that slow down insulin degradation.

Furthermore, a key advantage of using substrate-selective IDE modulators is their action on a physiological mechanism that is complementary to other FDA-approved drugs, which allows synergistic combinations with established treatments that increase insulin sensitivity (e.g. metformin) or insulin production (e.g. DPP4-i). Substrate-selective IDE inhibitors assist the body by boosting the insulin levels endogenously secreted by the pancreas in response to each meal composition. This mechanism has an advantageous safety profile with regards to hypoglycemic shock and Glucagon-driven hyperglycemia, and also protects beta-cell function on the long term, thus delaying the advance of late-stage Diabetes and the need for injectable insulin supplements.

Intellectual Property Status: Patent(s) Pending