Novel TXNIP degraders for treating diabetes

用于治疗糖尿病的新型 TXNIP 降解剂

基本信息

批准号：
10258437
负责人：
David E Sterner
金额：
$ 26.6万
依托单位：
PROGENRA, INC.
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-05 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10258437
关键词：
Affect Alabama American Animal Model Anti-Inflammatory Agents Antidiabetic Drugs Apoptosis Attenuated Autoimmune Autoimmune Diseases B-Lymphocytes Beta Cell Bioavailable Biological Assay Blood Glucose Calcium Channel Blockers Cell Line Cell physiology Cells Chemicals Clinical Data Development Diabetes Mellitus Diabetic mouse Disease Disease Management Dose Down-Regulation Drug Targeting Enzymes Exhibits Exposure to Feasibility Studies Goals Head Health Human Human Cell Line Inbred NOD Mice Inflammatory Institutes Insulin Insulin-Dependent Diabetes Mellitus Islet Cell Knock-out Mediating Metabolism Modeling Mus Non-Insulin-Dependent Diabetes Mellitus Oral Oxidation-Reduction Pathway interactions Patients Pharmaceutical Preparations Pharmacologic Substance Phase Physiological Processes Population Preclinical Drug Development Production Proteins Proteome Pruritus Regimen Regulatory Pathway Structure of beta Cell of islet System T-Lymphocyte TXNIP gene Testing Therapeutic Toxicology Tumor Suppressor Proteins Ubiquitin United States Universities Up-Regulation Verapamil Work base cell mediated immune response combat cytokine diabetes management diabetes mellitus therapy diabetic drug discovery efficacy study glucose metabolism glucose uptake high throughput screening improved in vivo inhibitor/antagonist islet knock-down mouse model multicatalytic endopeptidase complex novel preclinical development preservation prevent protein degradation small molecule therapeutic target ubiquitin-protein ligase

项目摘要

More than 30 million American have diabetes (~10% of the population), making it a major health issue. Available therapies for diabetics include insulin replacement or various drugs that modulate insulin production/sensitivity or reduce blood sugar levels by other mechanisms. For many patients, however, available treatments are limited by efficacy or convenience/compliance issues. Thus, alternative therapeutics, particularly those with novel mechanisms of action, are needed to manage diabetes, either as single agents or components of combination regimens. TXNIP (thioredoxin-interacting protein), a regulator of various aspects of metabolism, has emerged as a potential diabetes drug target. This protein regulates the cell’s redox state and reportedly acts as a tumor suppressor, in addition to regulating glucose metabolism. Notably, TXNIP knockdown leads to anti-diabetic effects in mice, so agents that inhibit TXNIP or reduce its concentration are potential therapies for diabetes. Protein content and activity in cells is regulated largely by the ubiquitin- proteasome system, through which conjugation and deconjugation of ubiquitin to and from target proteins attenuates or increases cell content or alters the protein’s activity through compartmentation or other means. The human proteome contains more than 600 ubiquitin E3 ligases (ubiquitin-ligating enzymes), many of which are validated therapeutic targets for drug discovery. TXNIP is ubiquitinated by the E3 ligase Itch and subsequently degraded in the proteasome. Activation of Itch, therefore, is a promising therapeutic strategy to attenuate TXNIP levels, increasing glucose uptake and dampening the diabetic state. The therapeutic hypothesis for the proposed project is that Itch is, in fact, a novel target for diabetes therapy, and activators of Itch can be found that will increase TXNIP degradation in cells and thereby combat diabetes. Through high throughput screening, Progenra has identified novel small molecule activators of Itch, of which one – P76251 – provided proof of concept for the therapeutic hypothesis by inducing robust TXNIP degradation in a human cell line in a concentration-dependent manner. In the feasibility study proposed here, P76251 will be tested for its ability to degrade TXNIP in human pancreatic beta cells (INS-1 cell line and isolated human islets), and in vivo proof of concept will be established for P76251 by assessment of its anti-diabetic effects in mice. In Phase II, preclinical development will continue with additional efficacy studies, chemical optimization, and ADME/PK and toxicology studies.

超过3000万美国人患有糖尿病（约占人口的10％），这是一个主要的健康问题。可用的糖尿病患者疗法包括胰岛素替代品或调节胰岛素的各种药物生产/敏感性或通过其他机制降低血糖水平。但是，对于许多患者，可用的治疗受效率或便利/合规性问题的限制。那是替代疗法，特别是那些具有新型作用机制的人，需要作为单一药物或组合方案的组成部分。 txnip（硫氧还蛋白相互作用蛋白），是各个方面的调节剂代谢已成为潜在的糖尿病药物靶标。该蛋白质调节细胞的氧化还原状态和据报道，除了反思葡萄糖代谢外，还充当肿瘤抑制剂。值得注意的是，txnip 敲低导致小鼠的抗糖尿病作用，因此抑制TXNIP或降低其浓度的药物是糖尿病的潜在疗法。细胞中的蛋白质含量和活性在很大程度上由泛素调节蛋白酶体系统，通过该系统，泛素蛋白与泛素的共轭和解偶联通过隔室或其他方式减弱或增加细胞含量或改变蛋白质的活性。人蛋白包含超过600个泛素E3连接酶（泛素绑扎酶），其中许多是经过验证的药物发现治疗靶标。 txnip被E3连接酶瘙痒泛滥成灾，因此，激活瘙痒是一种有前途的治疗策略减弱TXNIP水平，增加葡萄糖的摄取并使糖尿病状态造成轰动。治疗性拟议项目的假设是，瘙痒实际上是糖尿病治疗的新型靶标，以及激活剂的活化剂可以发现痒会增加细胞中的TxNIP降解，从而对抗糖尿病。通过高吞吐量筛选，后代已经确定了瘙痒的新型小分子活化剂，其中一个 - p76251 - 通过在人类细胞中诱导的鲁棒TxNIP降解提供了治疗假设的概念证明以浓度依赖的方式行。在此处提出的可行性研究中，将对P76251进行测试能够在人胰腺β细胞（INS-1细胞系和孤立的人类胰岛）和体内降解TxNIP的能力 P76251将通过评估其在小鼠中的抗糖尿病作用来确定概念证明。在第二阶段，临床前开发将继续进行其他效率研究，化学优化以及ADME/PK以及毒理学研究。