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 细胞质量扩张的药理学方法最近引起了我们团队和其他人的强烈研究兴趣。成功地进行了广泛的医学化学努力，开发了人类β细胞增殖的高效小分子诱导剂；然而，这些分子的生长促进活性是非选择性的，诱导脱靶细胞增殖的潜力是主要的。安全使用这些的障碍在这里，我们部署了一种创新的药物化学方法来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、货物输送以及因此的复制促进活性。限制性细胞酶能够作用于小分子底物，通过（目标 1）基于合理结构的设计和化学的迭代循环，选择性地将潜在前药转化为具有生物活性的子化合物。合成、执行严格的基于生化和细胞分析的筛选级联（具有明确的“go-no-go”标准），以及对可裂解可逆抑制部分进行递归优化（将其纳入经过验证的复制刺激原型中），我们将生成广泛的结构结构- 活性关系知识，并最终为 β 细胞靶向再生疗法提供早期治疗线索（目标 2），手中拥有经过生化和细胞分析验证的化合物，这些化合物源自至少两种成分不同的化合物。原型分子，我们将评估化合物毒性并解决任何代谢倾向和/或药代动力学弱点（目标 3）最后，我们将评估早期先导化合物在基于体内临床前人胰岛移植的治疗效果（恢复血糖控制）。糖尿病模型。将在短期（数天至数周）和长期（数月）化合物暴露研究后评估目标（β细胞）和非目标组织的复制活性；我们的 β 细胞靶向治疗策略的功效。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的、潜在变革性的一流先导化合物。，该策略广泛适用于通过靶向 β 细胞递送增强的任何治疗。