Type 2 diabetes (T2DM) is a chronic metabolic disease that affects the quality and longevity of life. Currently it is estimated that about 246 million people worldwide and diabetic and their number is expected to increase to 380 million by 2025. Further, the agents used to treat T2DM fail to exhibit the desired efficacy in Type 2 diabetics. Therefore, there is a significant unmet medical need for new and more efficacious antidiabetic agents that would display effective and sustained glucose lowering over number of years. Glucokinase Activators (GKAs) have emerged as a new class of pharmaceutical agents that have exhibited efficacy in a variety of animal models of Type 2 diabetes and several GKAs have entered clinical trials. Unfortunately, severe and debilitating adverse drug reactions were recently observed during clinical trials that studied the effects of GKA treatment in T2DM patients. In detail, GKA treatment resulted in hypoglycemia due to inappropriate insulin secretion and necessitated glucose infusion rescue therapy. Glucose independent insulin secretion is a hallmark of both the sulfonylureas and meglitinides insulin secretagogues that can result in hypoglycemia. Likewise, excessive activation of GKA would also result in inappropriate insulin secretion and hypoglycemia. Thus, we hypothesize that partial activation of GK will have a reduced potential for hypoglycemia in a clinical setting. Towards the identification of partial GKAs, Sorrento Technologies team has solved multiple crystal structures of human GK 9hGK) ternary complexes (hGK:glucose:GKA) using either full or partial GKAs bound to the allosteric site and glucose bound to the active site. From the resulting 3-dimentional information, a detailed structural model of full or partial GK activation is being developed. We intend to use this structural information to guide our identification of novel potent GKAs that only partially activate GK. In detail, novel GKAs will be evolved from either crystallographic and/or nanocalorimetry fragment-based screening. The evolution of fragment ligands into partial GKAs will be aided by both biochemical mode of activation analysis as well as Sorrento Technologies'rapid procedure to generate high quality structural data of novel hGK:glucose:GKA ternary complexes. After identification of several lead K-system GKA series, we intend to implement structure guided medicinal chemistry campaign to develop a partial GKAs with pharmaceutical like properties.
