Discovery of NV-5138, the first selective Brain mTORC1 activator

The mechanistic targetof rapamycincomplex 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 leucineare required for full mTORC1activation. The cytoplasmic proteins Sestrin1 and Sestrin2 specifically bind to the multiprotein complexGATOR2 and communicate leucinesufficiency to the mTORC1pathway activation complex. Herein, we report NV-5138, a novel orally bioavailable compound that binds to Sestrin2 and activates mTORC1both in vitro and in vivo. NV-5138 like leucinetransiently activates mTORC1in several peripheral tissues, but in contrast to leucineuniquely 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.