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 (mTORC1) 的机制靶点是 细胞生长。与 mTORC1 的重要性相称的是一个复杂的增长网络 因子信号传导和营养传感途径调节 mTORC1 活性，进而调节 mTORC1 活性 调节蛋白质合成和许多其他细胞过程。过度激活 mTORC1 信号传导是衰老疾病和病症的一个共同特征。 mTORC1 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、减少肥胖并逆转与年龄相关的 人类免疫下降，并在神经退行性啮齿动物模型中表现出活性， 心肌病、动脉粥样硬化、视网膜病和听力损失。 mTORC1 抑制剂 还能延长小鼠、蠕虫和酵母的寿命。我们发现了一种小分子 (CB3A) 通过一种新机制抑制 mTORC1 信号传导。与其他小 mTORC1、CB3A 的分子抑制剂优先降低 4EBP1相对于S6K。因此，CB3A 启发的药物可能为以下疾病提供治疗益处： 4EBP1 磷酸化是驱动因素的疾病/病症。这些 疾病/病症包括癌症、糖尿病和肌肉损失。然而，mTORC1 过度激活可能源自不同的潜在分子机制。所以 该项目的目标是阐明 CB3A 的作用机制。此信息 需要确定哪些疾病最有可能对 CB3A 启发的药物产生反应 治疗策略。我们的初步结果表明 CB3A 增加了泛素化 负 mTORC1 调节器 TSC2。尽管 TSC2 的监管 磷酸化已被广泛认可，但对于泛素化的作用知之甚少。 TSC2/mTORC1 调节。 CB3A本身不太可能具有治疗价值，但是 了解 CB3A 抑制机制可能会发现新的潜力 mTORC1 监管的目标以及新方面。