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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：
10215497
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/10215497
关键词：
Address B Cell Proliferation 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 Mixed Function Oxygenases Modeling Modification Mothers Mus Natural regeneration Non-Insulin-Dependent Diabetes Mellitus Obesity Epidemic Oral Pathologic Performance Permeability Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology 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 base 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/antagonist innovation interest islet meetings novel pre-clinical preclinical development prevent prototype regenerative regenerative therapy regenerative treatment restoration screening small molecule targeted treatment therapeutic candidate treatment strategy

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型糖尿病的特征在于β细胞质量的损失和胰岛素产生能力的降低。因此，开发用于刺激β细胞团扩增的药理学方法具有强烈的研究兴趣。最近，我们的团队和其他人已经成功地进行了广泛的医学化学工作，以开发高度有效的人类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可能性是这些再生化合物在人体中安全使用的主要障碍。在这里，我们部署了一个创新的药物化学努力，以开发一个原始的前药系统，使β细胞选择性化学活化，货物交付，因此，复制促进活动。我们将利用一种能够作用于小分子底物的高度加工性β细胞限制酶，在β细胞内选择性地将潜在前药转化为其生物活性子化合物。通过（目标1）基于合理结构的设计和化学合成的迭代循环，执行严格的基于生物化学和细胞测定的筛选级联，具有明确的go-no-go标准，以及递归优化可裂解的可逆抑制部分，这些部分被纳入验证的复制刺激原型中，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。(Aim 2）通过生物化学和细胞分析验证的化合物，衍生自至少两种组成不同的原型分子，我们将评估化合物毒性并解决任何代谢责任和/或药代动力学弱点。(Aim 3）最后，我们将评估早期先导化合物在体内临床前基于人胰岛移植的糖尿病模型中的治疗功效（恢复血糖控制）。将在短期（数天-数周）和长期（数月）化合物暴露后评估靶（β细胞）和脱靶组织的复制活性;研究对于证明我们的β细胞靶向治疗策略的持续特异性和疗效至关重要。这些新的β细胞选择性前药策略的早期临床前开发研究有可能提供安全的，潜在的变革性的，一流的先导化合物用于糖尿病的再生治疗。重要的是，该策略广泛适用于将通过靶向β细胞递送增强的任何治疗剂。