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

1型和2型糖尿病的特征是β细胞团的丧失和胰岛素生产能力的降低。因此，开发一种刺激β细胞团扩张的药理学方法具有重要的研究意义。最近，我们的团队和其他人成功地进行了广泛的药物化学努力，以开发高效的小分子诱导剂来促进人β细胞的增殖；然而，这些分子的促生长活性是非选择性的。因此，诱导靶外细胞增殖的可能性是在人类中安全使用这些再生化合物的主要障碍。在这里，我们部署了一种创新的药物化学努力，以开发一种原始的前药系统，该系统能够使β细胞选择性地化学激活、货物输送，从而具有促进复制的活性。我们将利用一种高度进行性的β细胞限制性酶，这种酶能够作用于小分子底物，在β细胞内选择性地将潜伏的前药转化为具有生物活性的子体化合物。通过(目标1)合理的基于结构的设计和化学合成的迭代循环，使用定义明确的go-no-go标准执行严格的基于生化和细胞分析的筛选级联，以及将可切割的可逆抑制部分合并到验证的复制刺激原型中进行递归优化，我们将产生广泛的结构活性关系知识，并最终为β细胞靶向再生治疗提供早期治疗线索。(目标2)有了生化和细胞分析验证的化合物，这些化合物来自至少两个成分不同的原型分子，我们将评估化合物的毒性，并解决任何代谢责任和/或药代动力学弱点。(目的3)最后，我们将评估早期先导化合物在基于临床前人类胰岛移植的体内糖尿病模型中的治疗效果(恢复血糖控制)。目标(β细胞)和非目标组织的复制活性将在短期(数天-数周)和长期(数月)复合暴露后进行评估；对于证明我们的β-细胞靶向治疗策略的持续特异性和有效性至关重要的研究。这些新的β细胞选择性前药物策略的早期临床前开发研究有可能为糖尿病的再生治疗提供安全的、潜在的变革性的、一流的先导化合物。关键的是，这一策略广泛适用于任何通过靶向β细胞递送而增强的治疗。

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.