A novel rapamycin analog is highly selective for mTORC1 in vivo
A novel rapamycin analog is highly selective for mTORC1 in vivo
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DOI：
10.1038/s41467-019-11174-0
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发表时间：
2019-07-19
影响因子：
16.6
通讯作者：
Lamming, Dudley W.
中科院分区：
文献类型：
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作者：
Schreiber, Katherine H.;Apelo, Sebastian I. Arriola;Lamming, Dudley W.
雷帕霉素是一种雷帕霉素复合体机制靶点1(MTORC1)的抑制剂，可延长寿命，并显示出治疗年龄相关性疾病的强大潜力。然而，雷帕霉素通过对第二个含有mTOR的复合体mTOR复合体2的靶外抑制而产生代谢和免疫副作用。在这里，我们报告了DL001的鉴定，它是一种依赖于FKBP12的雷帕霉素类似物，对mTORC1的选择性是雷帕霉素的40倍。DL001在细胞系和C57BL/6J小鼠体内抑制mTORC1，其中DL001在不损害葡萄糖稳态的情况下抑制mTORC1信号转导，并且对脂代谢和免疫系统的副作用显著减少或没有副作用。在细胞中，DL001有效地抑制mTORC1活性的升高，并恢复缺乏功能性结节性硬化症复合体的细胞的正常基因表达。我们的结果表明，在体内可以实现对mTORC1的高度选择性药理抑制，并且选择性抑制mTORC1显著减少了与传统雷帕罗格相关的副作用。
Rapamycin, an inhibitor of mechanistic Target Of Rapamycin Complex 1 (mTORC1), extends lifespan and shows strong potential for the treatment of age-related diseases. However, rapamycin exerts metabolic and immunological side effects mediated by off-target inhibition of a second mTOR-containing complex, mTOR complex 2. Here, we report the identification of DL001, a FKBP12-dependent rapamycin analog 40x more selective for mTORC1 than rapamycin. DL001 inhibits mTORC1 in cell culture lines and in vivo in C57BL/6J mice, in which DL001 inhibits mTORC1 signaling without impairing glucose homeostasis and with substantially reduced or no side effects on lipid metabolism and the immune system. In cells, DL001 efficiently represses elevated mTORC1 activity and restores normal gene expression to cells lacking a functional tuberous sclerosis complex. Our results demonstrate that highly selective pharmacological inhibition of mTORC1 can be achieved in vivo, and that selective inhibition of mTORC1 significantly reduces the side effects associated with conventional rapalogs.