Development of Beta-Cell-Targeted Regenerative Therapeutics Using A Novel Prodrug Strategy

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Type 1 and type 2 diabetes are characterized by the loss of β-cell mass and decreased insulin production capacity. Thus, developing a pharmacologic method for stimulating the expansion of β-cell mass is of intense research interest. Recently, our group and others have successfully undertaken extensive medical chemistry efforts to develop highly potent small-molecule inducers of human β-cell proliferation; however, the growth-promoting activity of these molecules is non-selective. Consequently, the potential for inducing off-target cellular proliferation is a primary barrier to the safe use of these regenerative compounds in humans. Here, we deploy an innovative medicinal chemistry effort to develop an original prodrug system that enables β-cell selective chemical activation, cargo delivery and, consequently, replication-promoting activity. We will take advantage of a highly processive, β-cell restricted enzyme that is capable of acting on small molecule substrates, to convert latent prodrugs to their biologically active daughter compounds selectively within β-cells. Through iterative cycles of (Aim 1) a rational structure-based design and chemical synthesis, execution of a rigorous biochemical- and cellular assay-based screening cascade with well-defined go-no-go criteria, and recursive optimization of cleavable reversibly-inhibitory moieties that are incorporated into validated replication stimulating prototypes, we will generate extensive structure-activity relationship knowledge and, ultimately, early therapeutic leads for β-cell-targeted regenerative therapy. (Aim 2) With biochemical- and cellular assay-validated compounds in hand, derived from at least two compositionally diverse prototypic molecules, we will assess compound toxicity and address any metabolic liabilities and/or pharmacokinetic weaknesses. (Aim 3) Finally, we will assess therapeutic efficacy (restoration of glycemic control) of early lead compounds in an in vivo preclinical human islet transplantation-based model of diabetes. The replicative activity of target (β-cells) and off-target tissues will be assessed following short-term (days-weeks) and long term (months) compound exposure; studies critical to demonstrating the sustained specificity and efficacy of our β-cell targeted therapeutic strategy. These early-stage preclinical development studies of a novel β-cell selective prodrug strategy have the potential to deliver safe, potentially transformative, first-in-class lead compounds for regenerative treatment of diabetes. Critically, this strategy is broadly applicable to any therapeutic that would be enhanced by targeted β-cell delivery.