Navitor is leveraging a proprietary biological understanding of cellular signaling pathways that lead to the activation of mTORC1 to develop selective modulators of its activity. This new approach will significantly expand the therapeutic potential of the clinically validated mTOR pathway to enable Navitor to address processes that drive chronic diseases of aging as well as rare diseases that are linked to the genetic dysregulation of mTORC1 activation, while avoiding undesirable side effects from chronic inhibition of mTORC2’s role in maintaining cellular health.
Both mTORC1 and mTORC2 are central players in a complex and interconnected network of signaling pathways that have been linked to different aspects of cellular function. mTORC1 is primarily responsible for the regulation of cell growth and fundamental biosynthetic processes, including protein and lipid synthesis. mTORC2 is critical for maintaining the sensitivity of cells to growth factors and for overall survival.
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To date, it had not been feasible to selectively target either mTORC1 or mTORC2. Navitor’s proprietary approach is based on groundbreaking discoveries related to the complex regulation of the mTOR pathway that enable the company to selectively target the activation of mTORC1. These discoveries have elucidated the role of specific nutrient and growth factor-mediated signaling pathways within the interconnected mTORC1 pathway network, and their effects on protein synthesis and cellular metabolism.
Navitor’s understanding of mTORC1’s distinct cellular signals and their biological roles enables the company to develop drugs that selectively target mTORC1 activation pathways to achieve highly targeted effects on diseases that involve dysregulation of protein synthesis and cellular metabolism. Furthermore, this detailed and proprietary understanding of regulating mTORC1 activation pathways will permit the discovery of new strategies for regulating abnormal disease processes by modulating mTORC1 activity across its spectrum of function.
mTORC1 is a clinically validated drug target and is central to the biology of aging and associated diseases—but clinical use has been limited due to inability to distinguish between mTORC1 and mTORC2
The first and one of most successful pharmacological agents to demonstrate lifespan extension in multiple species—including yeast, worms, flies, and mammals—is rapamycin, a natural product discovered nearly 30 years ago that targets the mTOR signaling pathway. Rapamycin works by inhibiting mTOR, resulting in increased catabolic processes (i.e., autophagy) that increase the cell’s ability to survive longer.
Rapamycin and various analogs (i.e., “rapalogs”) are approved and marketed for a variety of clinical applications, including antifungal, immunosuppression, anticancer, and as an anti-proliferative agent in coronary stents; and for use in diseases characterized by the genetic dysregulation of mTORC1 activation, including complications of tuberous sclerosis and lymphangioleiomyomatosis. In addition to the approved clinical applications, rapamycin and several rapalogs have demonstrated significant efficacy in a range of preclinical models of chronic disease, including metabolic disease, neurodegeneration, autoimmune disease, age-related immune suppression (i.e., immunosenescence), and mitochondrial disease. Many of these diseases can be classified as being associated with increasing age.
The versatility of rapamycin and rapalogs to treat a range of diseases of unrelated etiology and anti-aging effects across multiple species has been linked to the compound’s broad modulation through the mTOR kinase signaling network, primarily through the formation of an initial inhibitory complex with mTORC1. The effects of rapamycin on longevity and age-related diseases have been shown to be similar to the impacts of dietary (or caloric) restriction, which also manifests its effects primarily through the downregulation of mTORC1-mediated signaling—principally through reduced nutrient signaling.
The benefits of rapamycin and rapalogs on aging and associated diseases are clear, yet broad clinical use has been limited. Currently marketed drugs do not distinguish between mTORC1 and mTORC2, the individual cellular signaling complexes in the mTOR pathway. This lack of selectivity has led to undesirable side effects observed with chronic drug administration (including oral mucositis, metabolic dysfunction characterized by hyperlipemia, hyperglycemia, insulin resistance, immunosuppression, and others) due to inhibition of the function of mTORC2. The ability to selectively inhibit mTORC1 activation without affecting the activity or formation of the mTORC2 complex therefore opens important new therapeutic potential for this fundamental age-related disease pathway.
Navitor’s drug discovery platform is built upon the leading-edge insights of its scientific founder, David M. Sabatini, MD, PhD, whose discoveries relating to the mTORC1 pathway are seminal contributions to the field of cellular nutrient signaling. Through an exclusive license with the Whitehead Institute for Biomedical Research, Navitor has access to fundamental intellectual property and know-how from Dr. Sabatini’s laboratory related to activation of the mTORC1 pathway for use in pharmaceutical and other applications.
Navitor is developing innovative and proprietary drug discovery methodologies to interrogate cellular signals within the mTORC1 activation pathways. The company’s proprietary technology platform encompasses know-how, tools, and techniques that allow Navitor to uniquely address the complexity of mTORC1 activation pathways, including proprietary reagents and assays, targeted screening methods for mTORC1 therapeutic modulators, and unique pathway analyses for therapeutic targeting at key points in mTORC1 activation pathways.
Navitor’s proprietary IP, know-how, and drug discovery tools will enable the company to discover drugs that selectively modulate mTORC1 activation pathways with high specificity.