Beyond Rapamycin

Navitor’s proprietary drug discovery platform is designed to develop first-in-class selective modulators of mTORC1 activity, leveraging the known biology of rapamycin and related nonselective mTORC1/2 inhibitors.

The first and one of the most consistent pharmacological agents to demonstrate lifespan extension in multiple species—including yeast, worms, flies, and mammals—is rapamycin, a natural product discovered nearly 50 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 upregulation of mTORC1 activity. 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 diseases, neurodegeneration, autoimmune disease, age-related decline in immune function (i.e., immunosenescence), and mitochondrial disease. Many of these diseases can be classified as being directly associated with increasing age.

The versatility of rapamycin and rapalogs to treat a range of age-related diseases across multiple species has been linked to the compound’s broad modulation through the mTOR kinase signaling network, primarily by forming an inhibitory complex with mTORC1. The effects of rapamycin on longevity and age-related diseases are similar to the impacts of dietary (or caloric) restriction, which include downregulation of mTORC1-mediated signaling.

The benefits of rapamycin and rapalogs on aging and associated diseases are clear, yet broad clinical use has been limited. Currently marketed drugs inhibit both mTORC1 and mTORC2. This lack of selectivity drives undesirable side effects with chronic treatment 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 aging-related diseases.

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