Novel TXNIP degraders for treating diabetes

超过3000万美国人患有糖尿病(约占总人口的10%)，这使其成为一个主要的健康问题。 糖尿病患者的现有治疗方法包括胰岛素替代疗法或各种调节胰岛素的药物。 产生/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， 现有的治疗方法受到疗效或便利性/遵从性问题的限制。因此，另类疗法， 尤其是那些具有新作用机制的药物，需要作为单一药物或 联合疗法的组成部分。TXNIP(硫氧还蛋白相互作用蛋白)，一种多方面的调节 新陈代谢，已成为潜在的糖尿病药物靶点。这种蛋白质调节细胞的氧化还原状态，并 据报道，除了调节葡萄糖代谢外，它还起到了肿瘤抑制作用。值得注意的是，TXNIP 基因敲除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 糖尿病的潜在治疗方法。细胞中的蛋白质含量和活性在很大程度上受泛素- 蛋白酶体系统，通过该系统泛素与靶蛋白的结合和去结合 通过分隔或其他方式减少或增加细胞含量或改变蛋白质的活性。 人类蛋白质组包含600多种泛素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。血栓素NIP被E3连接酶Itch和 随后在蛋白酶体中降解。因此，激活瘙痒是一种很有前途的治疗策略 降低TXNIP水平，增加葡萄糖摄取，抑制糖尿病状态。治疗性 建议项目的假设是，实际上，瘙痒是糖尿病治疗的新靶点，而 可以发现，瘙痒会增加细胞中TXNIP的降解，从而对抗糖尿病。直通高 通过吞吐量筛选，Progenra已经发现了新型的瘙痒小分子激活剂，其中一种-P76251- 通过在人类细胞中诱导强大的TXNIP降解为治疗假说提供了概念证据 以一种浓度依赖的方式。在这里提出的可行性研究中，P76251将进行测试，以确定其 人胰岛β细胞(INS-1细胞系和分离的人胰岛)体内降解TXNIP的能力 通过评估P76251在小鼠中的抗糖尿病效果，将建立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和 毒理学研究。

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.