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

Abstract

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.

Human retinal ganglion cell axon regeneration by recapitulating developmental mechanisms: effects of recruitment of the mTOR pathway

“…Clinical targeting of the mTOR pathway to rescue RGC degeneration may involve pharmacological activation of the pathway. Recently, a small molecule, NV-5138, has been shown to activate mTORC1 both in vivo and in vitro (Kato et al, 2019;Sengupta et al, 2019). Alternatively, to address the concern that pharmacological activation of the mTOR pathway may affect the function of other cell types because of its ubiquitous presence, RGCs could be targeted for silencing the TSC2 gene by adeno-associated virus sera 2 (AAV2) transduction, which is RGC specific in the adult retina (Hanlon et al, 2017;Harvey et al, 2009).…”

Sestrin modulator NV-5138 produces rapid antidepressant effects via direct mTORC1 activation

“…For this study, rats were exposed to an additional 5 days of CUS after vation of this pathway produces rapid antidepressant responses. NV-5138 was designed as a synthetic leucine analogue that readily penetrates the blood-brain barrier and selectively binds sestrin to activate mTORC1 signaling in the brain (22). In addition, NV-5138 is highly selective for sestrin without modulation of other CNS targets, including binding to or functional modulation of NMDA receptors (22).…”

“…NV-5138 was designed as a synthetic leucine analogue that readily penetrates the blood-brain barrier and selectively binds sestrin to activate mTORC1 signaling in the brain (22). In addition, NV-5138 is highly selective for sestrin without modulation of other CNS targets, including binding to or functional modulation of NMDA receptors (22). NV-5138 is not a substrate for the key leucine metabolizing pathways and is not incorporated into proteins (22).…”

“…In addition, NV-5138 is highly selective for sestrin without modulation of other CNS targets, including binding to or functional modulation of NMDA receptors (22). NV-5138 is not a substrate for the key leucine metabolizing pathways and is not incorporated into proteins (22). These unique features of the compound result in rapid induction of mTORC1 activity in the brain via sestrin modulation.…”

NV-5138 as a fast-acting antidepressant via direct activation of mTORC1 signaling

“…Leucine, a critical amino acid in mTORC1-mediated protein synthesis, can bind sestrins, resulting in release from GATOR2, leading to mTORC1 activation (12). NV-5138 is a novel synthetic analog of leucine that has sufficient oral bioavailability and brain penetration to selectively bind sestrins for the activation of mTORC1 signaling in the brain (13). In this issue of the JCI, Kato et al report that oral administration of NV-5138 has a rapid and prolonged antidepressant action in rat models (14).…”