Inhibition of mTOR by a small molecule activator of TSC2

雷帕霉素复合体1的作用靶点(MTORC1)是一种主控调控因子 细胞生长。与mTORC1.S的重要性相称，一个复杂的成长网络 因子信号和营养感知通路调节mTORC1的活性，进而 调节蛋白质合成和许多其他细胞过程。过度激活 MTORC1信号是疾病和衰老状态的共同特征。 MTORC1抑制是治疗这些疾病的一种有前景的治疗策略。MTORC1 抑制剂增加改善预防癌症，减少肥胖和逆转与年龄相关的 在人类免疫功能下降和神经退行性变的啮齿动物模型中表现出活动， 心肌病、动脉粥样硬化、视网膜病和听力损失。MTORC1抑制剂 还可以延长小鼠、蠕虫和酵母的寿命。我们发现了一种小分子 (CB3A)通过一种新的机制抑制mTORC1信号转导。不像其他小的 MTORC1、CB3A分子抑制剂优先抑制细胞外信号转运蛋白的磷酸化 4EBP1相对于S6K。因此，受CB3A启发的药物可能会对 4EBP1磷酸化是驱动因素的疾病/状况。这些 疾病/状况包括癌症、糖尿病和肌肉萎缩。然而，mTORC1 过度激活可以来自不同的潜在分子机制。因此 本项目的目的是阐明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 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。虽然TSC2的调节是由 磷酸化是公认的，但对泛素化的作用知之甚少 TSC2/mTORC1调控。CB3A本身不太可能具有治疗价值，但 了解CB3A抑制的机制可能会发现新的潜力 MTORC1监管的目标以及新方面。

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.