Cellular senescence occurs when cells stop dividing, become metabolically over-active, accumulate morphological changes and begin to overexpress proinflammatory and pro-oxidant signals a condition termed senescence-associated secretory phenotype (or “SASP”).  Hyperactive mTORC1 signaling due to defects in amino acid and growth factor sensing and increased autophagy promotes cellular senescence.

Accumulating evidence suggests that senescent cells contribute to multiple age-related diseases.  Inhibition of the mTOR pathway by rapamycin delays the progression of cellular senescence and SASP which may, in part, account for its ability to prolong lifespan in model organisms.

Navitor’s highly selective mTORC1 inhibitors have the potential to reduce hyperactive mTORC1 signaling and thus cellular senescence without rapamycin’s undesirable side effects resulting from complete mTORC1 and partial mTORC2 inhibition.

Lymphangioleiomyomatosis (LAM) and Tuberous Sclerosis Complex (TSC) are rare diseases caused by specific genetic defects in the mTORC1 activation pathway, resulting in an uncontrolled hyperactivity of this complex that leads to abnormal cell and tumor growth.

Leigh’s syndrome, Friedrich’s ataxia, and other rare metabolic and mitochondrial diseases in which protein synthesis and/or cell growth have gone awry also involve hyperactive mTORC1 activation.

Navitor’s mTORC1 inhibitors have the potential to restore more normal function by specifically inhibiting the central process leading to these diseases.

Type 2 diabetes, obesity and other metabolic diseases in which hyperactive mTORC1 activity is driven through the excess availability of nutrients and is thought to cause dysregulated cellular function and drive the disease process.

Navitor’s mTORC1 inhibitors have the potential to improve insulin sensitivity and b-cell survival in metabolic diseases by specifically inhibiting the central process contributing to the nutrient-mediated pathology.

A broad range of cancers involve hyperactive mTOR pathway activity and excessive and unrestrained protein synthesis which enables proliferation of cancer cells. Multiple first-generation mTOR inhibitors (rapamycin and related analogs) are approved for a limited set of cancer indications.

Navitor’s highly specific mTORC1 inhibitors have the potential to offer improved efficacy and safety vs. earlier generation inhibitors that also inhibit mTORC2.

Alzheimer’s, Parkinson’s, and Huntington’s diseases and other neurodegenerative diseases that involve abnormal protein folding, possibly due to excessive and unrestrained protein synthesis.

Navitor’s mTORC1 inhibitors have the potential to restore more normal function by specifically inhibiting a central process contributing to the pathology of these diseases.

Fibrosis is a disease of metabolism of fibroblasts which causes the thickening and scarring of connective tissue. Fibrosis can occur in many tissues in the body such as the lung, liver and heart, and may ultimately cause disease by altering the architecture and function of the underlying organ or tissue.

Myofibroblasts found in fibrotic foci in the lung and kidney typically have hyperactive mTOR pathway activity. Genetic or pharmacological inhibition of mTOR can prevent activation of myofibroblasts and secretion of extracellular matrix in experimental models and prevent fibrosis.

Navitor’s fibrosis program targets the selective inhibition of mTORC1 signaling through the modulation of glucose metabolism and has demonstrated efficacy in a validated model of pulmonary fibrosis.

Immunosenesence, the age-related decline in immune function, results in increased susceptibility to infections and decreased immune response to vaccinations in aged individuals.

Immuno-oncology approaches aim to restore and/or augment the body’s immune-mediated destruction of cancerous cells. Metabolic dysfunction of T cells, which leads to impaired immune function, can be reversed by genetic activation of mTORC1, a key regulator of Th17 cells.

Psoriasis, rheumatoid arthritis, lupus, multiple sclerosis, and other autoimmune diseases in which increased mTORC1 activity is thought to contribute to the activation of a specific subpopulation of T-cells that may create inflammation and tissue injury.

Navitor therapeutics have potential in multiple immune-metabolism applications as either stand-alone or adjunctive agents by enhancing cell-mediated immune function including memory T cell responses to vaccination, solid tumor-directed or self-reactive immune cell-directed T cell immunotherapy.

Sarcopenia, Cachexia and other musculoskeletal conditions that involve muscle loss, such as following immobilization and due to aging, in which protein synthesis and/or cell growth is deficient.

Navitor mTORC1 activators have the potential to increase muscle protein synthesis and muscle function in multiple musculoskeletal indications.

Certain rare genetic disorders with a high prevalence of autism (e.g. Rett syndrome, SHANK3 mutations) involve reduced mTORC1 signaling, which is critical to normal synaptic formation and function in neurons, contributing to the neuropathology of autism.

Navitor mTORC1 activators have been demonstrated to increase synaptogenesis and improve synaptic signaling and could have positive effects on autistic behavior.

Depression, Cognition/Memory and other neuropsychiatric disorders: stressors and other factors reduce mTORC1 signaling and thus neural synaptogenesis and synaptic signaling in key regions of the brain including the pre-frontal cortex and hippocampus which leads to a cascade of events that can result in depression, cognitive defects and memory problems.

Navitor’s lead mTORC1 activator, NV-5138, is a first-in-class, oral small molecule mTORC1 activator targeting the leucine nutrient sensor. NV-5138 directly activates the mTORC1 pathway in neurons leading to increased synaptogenesis, improved synaptic signaling and anti-depressive behavioral effects that last for up to 1 week in animal models.