Mahoney Sarah J, Narayan Sridhar, Molz Lisa, Berstler Lauren A, Kang Seong A, Vlasuk George P, Saiah Eddine
Navitor Pharmaceuticals, Inc., 1030 Massachusetts Ave. #410, Cambridge, MA, 02138, USA.
Nat Commun. 2018 Feb 7;9(1):548. doi: 10.1038/s41467-018-03035-z.
The small G-protein Rheb activates the mechanistic target of rapamycin complex 1 (mTORC1) in response to growth factor signals. mTORC1 is a master regulator of cellular growth and metabolism; aberrant mTORC1 signaling is associated with fibrotic, metabolic, and neurodegenerative diseases, cancers, and rare disorders. Point mutations in the Rheb switch II domain impair its ability to activate mTORC1. Here, we report the discovery of a small molecule (NR1) that binds Rheb in the switch II domain and selectively blocks mTORC1 signaling. NR1 potently inhibits mTORC1 driven phosphorylation of ribosomal protein S6 kinase beta-1 (S6K1) but does not inhibit phosphorylation of AKT or ERK. In contrast to rapamycin, NR1 does not cause inhibition of mTORC2 upon prolonged treatment. Furthermore, NR1 potently and selectively inhibits mTORC1 in mouse kidney and muscle in vivo. The data presented herein suggest that pharmacological inhibition of Rheb is an effective approach for selective inhibition of mTORC1 with therapeutic potential.
小G蛋白Rheb响应生长因子信号激活雷帕霉素机制靶点复合物1（mTORC1）。mTORC1是细胞生长和代谢的主要调节因子；异常的mTORC1信号传导与纤维化、代谢和神经退行性疾病、癌症及罕见疾病相关。Rheb开关II结构域中的点突变会损害其激活mTORC1的能力。在此，我们报告发现了一种小分子（NR1），它在开关II结构域中与Rheb结合并选择性阻断mTORC1信号传导。NR1强烈抑制mTORC1驱动的核糖体蛋白S6激酶β-1（S6K1）磷酸化，但不抑制AKT或ERK的磷酸化。与雷帕霉素不同，长时间处理后NR1不会导致mTORC2受到抑制。此外，NR1在体内能有效且选择性地抑制小鼠肾脏和肌肉中的mTORC1。本文提供的数据表明，对Rheb进行药理学抑制是选择性抑制mTORC1的一种有效方法，具有治疗潜力。
