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

使用新型前药策略开发β细胞靶向再生疗法

基本信息

批准号：
10661006
负责人：
Justin Pierce Annes
金额：
$ 42.68万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10661006
关键词：
Address Beta Cell Biochemical Biological Biological Assay Biological Availability Cell Proliferation Cellular Assay Chemicals Chemistry Data Daughter Development Diabetes Mellitus Diabetic mouse Disease Drug Delivery Systems Drug Kinetics Drug Targeting Enzymes Functional disorder Genes Goals Half-Life Hand Hepatocyte Histology Human In Vitro Incidence Insulin Insulin-Dependent Diabetes Mellitus Investments Islets of Langerhans Transplantation Knowledge Lead Measurement Measures Medical Metabolic Methods Microsomes Modeling Modification Mothers Mus Natural regeneration Non-Insulin-Dependent Diabetes Mellitus Obesity Epidemic Oral Pathologic Performance Permeability Pharmaceutical Chemistry Pharmaceutical Preparations Plasma Pre-Clinical Model Process Prodrugs Production Property Protein Tyrosine Kinase Recombinants Research Rodent Safety Scheme Secretory Vesicles Serum Specificity Structure Structure-Activity Relationship System Technology Therapeutic Therapeutic Uses Tissues Toxic effect Toxicology Transplantation Treatment Efficacy Work blood glucose regulation cell type cellular targeting chemical synthesis clinical candidate design endocrine pancreas development experimental study glucose tolerance glycemic control growth promoting activity humanized mouse in vivo inhibitor innovation interest islet meetings novel peptidylglycine alpha-amidating monooxygenase pharmacologic pre-clinical preclinical development prevent prototype regenerative regenerative therapy regenerative treatment restoration screening small molecule targeted treatment therapeutic candidate treatment strategy type I and type II diabetes

项目摘要

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.

1型和2型糖尿病的特点是β细胞质量损失和胰岛素生产能力下降。因此，开发一种刺激β细胞团扩增的药理学方法是一个非常重要的研究课题。最近，我们的团队和其他团队已经成功地进行了广泛的医学化学努力，开发了高效的人类β细胞增殖的小分子诱导剂；然而，这些分子的促生长活性是非选择性的。因此，诱导脱靶细胞增殖的潜力是这些再生化合物在人类中安全使用的主要障碍。在这里，我们部署了一项创新的药物化学工作，以开发一种原始的前药系统，该系统能够实现β细胞的选择性化学激活，货物递送，从而促进复制活性。我们将利用一种高度程序化的β细胞限制性酶，它能够作用于小分子底物，在β细胞内选择性地将潜在的前药转化为具有生物活性的子化合物。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，执行严格的基于生化和细胞分析的筛选级联，具有明确定义的go- not -go标准，并将可切割的可逆抑制部分递归优化纳入验证的复制刺激原型，我们将产生广泛的结构-活性关系知识，最终，β细胞靶向再生治疗的早期治疗线索。（目标2）通过生化和细胞分析验证的化合物，从至少两种不同组成的原型分子中提取，我们将评估化合物的毒性，并解决任何代谢缺陷和/或药代动力学缺陷。（目的3）最后，我们将评估早期先导化合物在体内基于人类胰岛移植的糖尿病临床前模型中的治疗效果（恢复血糖控制）。在短期（天-周）和长期（月）化合物暴露后，将评估靶细胞（β细胞）和非靶组织的复制活性；研究对证明我们的β细胞靶向治疗策略的持续特异性和有效性至关重要。这些新型β细胞选择性前药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，具有潜在变革性的一流先导化合物。关键的是，这种策略广泛适用于任何通过靶向β细胞递送来增强的治疗。