Developing Inhibitors of the STARS/SRF Pathway for Treatment of Type 2 Diabetes

描述（由申请人提供）：2型糖尿病（T2D）在美国已经达到流行病的程度，影响了大约8.3%的人口。不幸的是，大多数糖尿病患者的血糖控制仍处于次优状态，因此迫切需要新的和改进的预防和治疗方法。Joslin糖尿病中心（JDC）的Mary Elizabeth Patti博士的实验室最近在人类t2dm患者的骨骼肌中发现了一种新的基因表达模式。这种模式包括受血清反应因子（SRF）及其上游调控蛋白STARS （rho依赖性信号的横纹肌激活因子）调控的基因表达增加。重要的是，这种模式也存在于基于家族史的疾病风险人群中，可能与t2d风险有关。来自Patti实验室（JDC）的遗传和药理学数据有力地表明，STARS-SRF通路的调节可以调节肌肉胰岛素抵抗和代谢，因此可能成为糖尿病治疗新药开发策略的重要靶点。通过降低STARS的表达或使用小分子SRF抑制剂CCG-1423，在培养的肌管中抑制STARS-SRF可改善氧化代谢并增加胰岛素刺激的葡萄糖运输。此外，在小鼠中抑制这一途径也可以改善代谢结果：(1)STARS-null小鼠对饮食诱导的肥胖和葡萄糖耐受性有抵抗力，可能通过增加运动能力和能量消耗（并且看起来更健康）；(2)用SRF抑制剂CCG-1423治疗小鼠使饮食诱导的肥胖小鼠的葡萄糖耐受性正常化。在第一阶段，Jenesis Biosciences（前身为Joslin Ventures， LLC）将与Patti博士（JDC）合作，进一步验证和表征这一令人兴奋的新靶点的治疗效用。我们已经有两种SRF-抑制剂（CCG-1423及其类似物，203,971）将用于a)阐明精确的分子靶点，b)研究体外机制依赖性毒性，以及c)在饮食诱导和遗传易感小鼠模型中进行体内概念验证（并评估体内毒性）。完成这一I期建议，将使我们能够最终评估这一途径是否适合药物干预。这将通过研究机制依赖性毒性和了解ccg化合物的治疗窗口来实现。ccg - 203971似乎具有3倍的效力（d0.15mg/kg/天），改善的溶解度，并且在一项中导体内研究中，100mg/kg/天（持续一周）似乎没有显示出不良反应，表明有一个很好的治疗窗口期。该信息及其靶亲和力（itc衍生的Kd）将用于评估其作为2期药物化学优化先导化合物的潜力，届时将产生更有效的类似药物的类似物，并评估药代动力学标准以及深入的安全性/毒性研究。该STTR的长期目标是开发新的、靶向的、安全的、有效的STARS-SRF通路抑制剂，这些抑制剂可能成为ind研究的候选药物。

DESCRIPTION (provided by applicant): Type 2 diabetes (T2D) has reached epidemic proportions in the United States, affecting an estimated 8.3% of the population. Unfortunately, the majority of individuals with diabetes continue to have suboptimal control of glucose, therefore new and improved approaches to prevention and treatment are sorely needed. Dr. Mary Elizabeth Patti's laboratory at the Joslin Diabetes Center (JDC) has recently identified a novel pattern of gene expression in skeletal muscle from human patients with established T2D. This pattern includes increased expression of genes regulated by serum response factor (SRF) and its upstream regulatory protein STARS (striated muscle activator of Rho-dependent signaling). Importantly, this pattern is also present in those at risk for disease based on family history, potentially linking this to T2D-risk. Genetic and pharmacologic data from the Patti lab (JDC) robustly indicate that modulation of the STARS-SRF pathway can regulate muscle insulin resistance and metabolism, and thus may serve as an important target for novel drug development strategies for diabetes management. Inhibition of STARS-SRF in cultured myotubes by either reduced expression of STARS or use of the small molecule SRF inhibitor CCG-1423 improves oxidative metabolism and increases insulin stimulated glucose transport. Moreover, inhibition of this pathway in mice also improves metabolic outcomes: (1) STARS-null mice are resistant to diet-induced obesity and glucose intolerance, potentially via increased exercise capacity and energy expenditure (and appear healthier) and (2) treatment of mice with the SRF inhibitor CCG-1423 normalizes glucose tolerance in mice with diet-induced obesity. In this Phase I, Jenesis Biosciences (formerly Joslin Ventures, LLC) will further validate and characterize this exciting new target in collaboration with Dr. Patti (JDC) for its therapeutic utiity. We already have two SRF- inhibitors (CCG-1423 and its analog, 203,971) that will be used to a) elucidate the precise molecular target, b) investigate mechanism dependent toxicity in vitro, and c) demonstrate in vivo proof-of-concept in both diet- induced and genetically predisposed mouse models (and evaluate in vivo toxicity). Completion of this Phase I proposal, will enable us to conclusively assess whether this pathway is amenable to medicinal intervention. This will be achieved by studying mechanism-dependent toxicity and understanding the therapeutic window of CCG-compounds. CCG-203,971 appears to have 3x greater potency (d0.15mg/kg/day), improved solubility and does not appear to show adverse effects in a pilot in vivo study at 100mg/kg/day (for a week) indicating an excellent therapeutic window. This information coupled with its target affinity (ITC-derived Kd) will be used to assess its potential as a Lead compound for Medicinal Chemistry optimization in Phase 2, where more potent, drug-like analogs will be generated and evaluated for pharmacokinetic criteria alongside in-depth safety/toxicity studies. The long-term objective of this STTR is to develop novel, targeted, safe and potent inhibitors of the STARS-SRF pathway that may become drug candidates for IND-enabling studies.