Navitor Pharmaceuticals, Inc., 1030 Massachusetts Ave. #410, Cambridge, MA, 02138, USA.
Sci Rep. 2019 Mar 11;9(1):4107. doi: 10.1038/s41598-019-40693-5.
The mechanistic target of rapamycin complex 1 (mTORC1) has been linked to several important chronic medical conditions many of which are associated with advancing age. A variety of inputs including the amino acid leucine are required for full mTORC1 activation. The cytoplasmic proteins Sestrin1 and Sestrin2 specifically bind to the multiprotein complex GATOR2 and communicate leucine sufficiency to the mTORC1 pathway activation complex. Herein, we report NV-5138, a novel orally bioavailable compound that binds to Sestrin2 and activates mTORC1 both in vitro and in vivo. NV-5138 like leucine transiently activates mTORC1 in several peripheral tissues, but in contrast to leucine uniquely activates this complex in the brain due lack of metabolism and utilization in protein synthesis. As such, NV-5138 will permit the exploration in areas of unmet medical need including neuropsychiatric conditions and cognition which have been linked to the activation status of mTORC1.
雷帕霉素靶蛋白复合物 1（mTORC1）的作用机制已与多种重要的慢性疾病相关联，其中许多疾病都与年龄增长有关。mTORC1 的完全激活需要多种输入，包括氨基酸亮氨酸。细胞质蛋白 Sestrin1 和 Sestrin2 特异性结合到多蛋白复合物 GATOR2，并将亮氨酸充足情况传递给 mTORC1 途径激活复合物。在此，我们报告了 NV-5138，这是一种新型的口服生物可利用化合物，可与 Sestrin2 结合并在体外和体内激活 mTORC1。NV-5138 像亮氨酸一样短暂激活几种外周组织中的 mTORC1，但与亮氨酸不同，由于缺乏代谢和用于蛋白质合成，NV-5138 可独特地激活大脑中的该复合物。因此，NV-5138 将允许探索包括神经精神疾病和认知在内的未满足医疗需求领域，这些领域与 mTORC1 的激活状态有关。
