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.

雷帕霉素复合物1（mTORC1）的机械目标已与几种重要的慢性医学疾病相关，其中许多疾病与年龄增长有关。完整的mTORC1激活需要多种输入，包括氨基酸亮氨酸。细胞质蛋白Sestrin1和Sestrin2与多蛋白复合物GATOR2特异性结合，并向mTORC1途径激活复合物传达亮氨酸充足性。在本文中，我们报告了NV-5138，这是一种新颖的口服生物利用性化合物，可与Sestrin2结合并在体外和体内激活mTORC1。NV-5138像亮氨酸可在几个周围组织中瞬时激活mTORC1，但与亮氨酸相反，由于缺乏新陈代谢和蛋白质合成利用，因此可在大脑中唯一激活此复合物。因此，NV-5138将允许在未满足的医疗需求领域中进行探索，包括与mTORC1的激活状态有关的神经精神疾病和认知。