Therapy Areas: Inflammatory Diseases
Peer-Reviewed Publication Details the Discovery and Development of Navitor Pharmaceuticals' NV-5138
11 March 2019 - - A peer-reviewed article in the Nature journal Scientific Reports detailis the discovery and characterisation of NV-5138 as a potential therapy for treatment-resistant depression, US-based mTORC1-targeted therapeutics developer Navitor Pharmaceuticals, Inc said.

NV-5138 is a first-in-class, orally-active small molecule that directly activates mTORC1, the gatekeeper of cellular metabolism and renewal, which is suppressed in the brain of people suffering from depression. NV-5138 is currently in Phase 1 development for the treatment of TRD, with top-line results expected in mid-2019.

Navitor's scientific founder, David M. Sabatini, M.D., Ph.D., Professor of Biology at the Massachusetts Institute of Technology, Member of Whitehead Institute for Biomedical Research, and Investigator of the Howard Hughes Medical Institute, discovered and characterized sestrin1 and 2 proteins (sestrin), which function as cellular sensors for the amino acid leucine, a natural activator of the mTORC1 pathway.

NV-5138 was designed by Navitor to specifically bind to sestrin and activate mTORC1. Unlike leucine, however, NV-5138 is able to effectively activate mTORC1 in the brain, which makes it uniquely suited to target disorders of the CNS where there is reduced mTORC1 pathway activity.

The article, title "Discovery of NV-5138, the first selective Brain mTORC1 activator" is published in the latest edition of the peer-reviewed journal Scientific Reports, an online, open access journal from the publishers of Nature, which publishes scientifically valid primary research from all areas of the natural and clinical sciences. The paper can be found at www.nature.com/articles/s41598-019-40693-5.

NV-5138 is an orally bioavailable, small molecule that directly and transiently activates mTORC1, the master modulator of cellular metabolism, which is often suppressed in the brain of patients suffering from depression.

NV-5138 binds to and modulates sestrin, a newly discovered cellular sensor protein for the amino acid leucine, a potent natural activator of mTORC1.

As opposed to many other organ systems like skeletal muscle, leucine is a poor activator of mTORC1 in the brain since it is principally used as a metabolic precursor for neurotransmitter and protein synthesis.

NV-5138 was designed to avoid the metabolic fate of leucine in the brain and thus serves as an effective activator of mTORC1 in this tissue.

Results from preclinical models demonstrate that oral administration of NV-5138 produces rapid upregulation of key synaptic proteins, synaptic remodeling in the prefrontal cortex and hippocampus, sustained antidepressant behavioral responses, cognitive improvements and compound-specific spectral power changes, as measured by quantitative electroencephalography.

Navitor's strong intellectual property portfolio includes composition of matter patent protection for NV-5138 and related compounds.

mTORC1, or Complex 1 of the mechanistic target of rapamycin, activity governs the pace and ability of the cell to synthesize protein and other cellular components. Increased mTORC1 activity contributes to a broad array of diseases of aging by increasing protein misfolding and driving cellular stress, inflammation, and fibrosis.

In other disease states such as severe depression, inadequate mTORC1 activity contributes to disease pathology by limiting energy utilisation and protein synthesis, leading to impaired function.

Multiple preclinical studies have shown that mTORC1 activation is required for the efficacy of many rapid-acting antidepressant compounds, including but not limited to modulators of the N-methyl-D-aspartic-acid -mediated signaling pathway like ketamine.

Navitor Pharmaceuticals, Inc. is a leader in the development of mTORC1-targeted therapeutics designed to help patients live longer and healthier lives.

The company's proprietary platform enables true modulation of mTORC1, the gatekeeper of cellular metabolism and renewal, with the first-ever absolutely selective mTORC1 inhibition and the unique ability for mTORC1 activation.

Navitor's lead clinical-stage candidate, NV-5138, is a small molecule that directly activates mTORC1 and is being developed for treatment-resistant depression, with additional opportunities in cognition and memory.

The company's NΛValog programme, which provides unprecedented selectivity in mTORC1 inhibition, is initially targeting chronic kidney disease and has broad potential application for age-related diseases.
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