Inhibition of mTOR by a small molecule activator of TSC2

TSC2 小分子激活剂对 mTOR 的抑制

• 批准号: 9976416
• 负责人: Lizbeth K. Hedstrom
• 金额: $ 24.26万
• 依托单位: BRANDEIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-15 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9976416
• 关键词: Address; Age; Aging; Atherosclerosis; Binding; Cardiomyopathies; Cell physiology; Cells; Characteristics; Complex; Diabetes Mellitus; Disease; Epidemic; FRAP1 gene; GTPase-Activating Proteins; Generations; Goals; Growth Factor; Guanosine Triphosphate; Human; Immune; Lead; Longevity; Lysosomes; Malignant Neoplasms; Modeling; Molecular; Mus; Muscular Atrophy; Nature; Nerve Degeneration; Obesity; Pathway interactions; Pharmaceutical Preparations; Phosphorylation; Process; Protein Biosynthesis; Proteins; Proteomics; Regulation; Resistance; Retinal Diseases; Rodent Model; Role; Signal Transduction; Sirolimus; Site; TSC2 gene; Testing; Therapeutic; Toxic effect; Ubiquitination; Yeasts; age related; analog; baby boomer; base; cell growth; cell growth regulation; detection of nutrient; experimental study; hearing impairment; improved; inhibitor/antagonist; knock-down; mouse model; novel; prevent; side effect; small molecule; small molecule inhibitor; treatment strategy; ubiquilin

The mechanistic target of rapamycin complex 1 (mTORC1) is a master regulator of cell growth. Commensurate with mTORC1's importance, a complex network of growth factor signaling and nutrient sensing pathways regulate mTORC1 activity, which in turn regulates protein synthesis and many other cellular processes. Hyperactivation of mTORC1 signaling is a common feature of the diseases and conditions of aging. mTORC1 inhibition is a promising treatment strategy for these diseases. mTORC1 inhibitors increase improve prevent cancer, decrease obesity and reverse age-related immune decline in humans and display activity in rodent models of neurodegeneration, cardiomyopathy, atheroscelerosis, retinopathy and hearing loss. mTORC1 inhibitors also increase lifespan in mice, worms and yeast. We have discovered a small molecule (CB3A) that inhibits mTORC1 signaling via a novel mechanism. Unlike other small molecule inhibitors of mTORC1, CB3A preferentially decreases the phosphorylation of 4EBP1 relative to S6K. Thus CB3A-inspired drugs may provide a therapeutic benefit for diseases/conditions where 4EBP1 phosphorylation is the driver. These diseases/conditions include cancer, diabetes and muscle loss. However, mTORC1 hyperactivation can derive from diverse underlying molecular mechanisms. Therefore the goal of this project is to elucidate the mechanism of CB3A action. This information is required to identify which diseases are most likely to respond to a CB3A-inspired treatment strategy. Our preliminary results show that CB3A increases the ubiquitination of the negative mTORC1 regulator TSC2. Although the regulation of TSC2 by phosphorylation is well recognized, little is known about the role of ubiquitination in TSC2/mTORC1 regulation. CB3A itself is unlikely to have therapeutic value, but understanding the mechanism of CB3A inhibition is likely to identify new potential targets as well as new facets of mTORC1 regulation.

雷帕霉素复合物1（mTORC 1）的机制靶点是一个主要的调节因子， 细胞生长与mTORC 1的重要性相称，一个复杂的生长网络 因子信号传导和营养传感途径调节mTORC 1活性， 调节蛋白质合成和许多其他细胞过程。超活化 mTORC 1信号传导是衰老疾病和病症的共同特征。 mTORC 1抑制是这些疾病的一种有前途的治疗策略。mTORC1 抑制剂增加改善预防癌症，减少肥胖和逆转年龄相关的 在人类免疫下降和啮齿动物神经变性模型中显示活性， 心肌病、动脉粥样硬化、视网膜病变和听力损失。mTORC 1抑制剂 也能延长老鼠蠕虫和酵母菌的寿命我们发现了一种小分子 （CB 3A），其通过新机制抑制mTORC 1信号传导。与其他小型 mTORC 1、CB 3A的分子抑制剂优先降低 4 EBP 1相对于S6 K。因此，CB 3A启发的药物可能会为以下患者提供治疗益处 疾病/病症，其中4 EBP 1磷酸化是驱动因素。这些 疾病/病症包括癌症、糖尿病和肌肉损失。mTORC1 超活化可以源自不同的潜在分子机制。因此 本研究的目的是阐明CB 3A的作用机制。这些信息 需要确定哪些疾病最有可能对CB 3A激发的 治疗策略我们的初步结果表明，CB 3A增加了泛素化， 负mTORC 1调节器TSC 2。虽然TSC 2的调节 磷酸化是公认的，但关于泛素化的作用知之甚少。 TSC 2/mTORC 1调节。CB 3A本身不太可能具有治疗价值，但 了解CB 3A抑制的机制可能会发现新的潜力， 目标以及mTORC 1调控的新方面。