Novel TXNIP degraders for treating diabetes

用于治疗糖尿病的新型 TXNIP 降解剂

• 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
• 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

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%），使其成为主要的健康问题。 糖尿病患者可用的治疗方法包括胰岛素替代或各种调节胰岛素的药物 生产/敏感性或通过其他机制降低血糖水平。然而，对于许多患者来说， 可用的治疗受到功效或便利性/顺应性问题的限制。因此，替代疗法， 特别是具有新作用机制的药物，需要作为单一药物或 联合治疗方案的组成部分。TXNIP（硫氧还蛋白相互作用蛋白），一种调节各种方面的 代谢，已成为一个潜在的糖尿病药物的目标。这种蛋白质调节细胞的氧化还原状态， 据报道，除了调节葡萄糖代谢外，还可作为肿瘤抑制因子。值得注意的是，TXNIP 敲低在小鼠中导致抗糖尿病作用，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主要由泛素- 蛋白酶体系统，通过该系统，泛素与靶蛋白的缀合和去缀合 通过区室化或其它方式减弱或增加细胞内容物或改变蛋白质的活性。 人类蛋白质组包含超过600种泛素E3连接酶（泛素连接酶），其中许多 是药物发现的有效治疗靶点。TXNIP被E3连接酶Itch泛素化， 随后在蛋白酶体中降解。因此，激活瘙痒是一种有前途的治疗策略， 降低TXNIP水平，增加葡萄糖摄取并抑制糖尿病状态。治疗 该项目的假设是，瘙痒实际上是糖尿病治疗的一个新靶点， 可以发现瘙痒会增加细胞中TXNIP的降解，从而对抗糖尿病。通过高 通过通量筛选，Progenra已鉴定出新型瘙痒小分子激活剂，其中之一- P76251 - 通过在人细胞中诱导强大的TXNIP降解，为治疗假设提供了概念证明 以浓度依赖的方式。在这里提出的可行性研究中，将测试P76251的 在人胰腺β细胞（INS-1细胞系和分离的人胰岛）中和体内降解TXNIP的能力 将通过评估P76251在小鼠中的抗糖尿病作用来建立P76251的概念验证。在第二阶段， 临床前开发将继续进行额外的疗效研究、化学优化和ADME/PK， 毒理学研究。