The mediation of mTORC1
New findings open opportunities for creating new medicines for metabolic, musculoskeletal, autoimmune and other age-related diseases
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CAMBRIDGE, Mass.—Navitor Pharmaceuticals Inc., a biopharmaceutical company developing novel medicines targeting the activation of mTORC1, recently announced that the company’s scientific founder, Dr. David M. Sabatini, published groundbreaking research describing, for the first time, the identification and characterization of the cellular proteins responsible for sensing and mediating the metabolic effects of the amino acid leucine.
The paper, published Oct. 8 online in the journal Science, elucidates a key regulatory node related to leucine that was previously unknown within the multiple steps of the mTORC1 activation pathway. The anabolic amino acid leucine is critical in cellular protein and lipid synthesis and directly regulates mammalian physiology including skeletal muscle growth, insulin secretion and food intake. As such, the ability to pharmacologically target the newly discovered sensor for leucine opens a potential avenue for the modulation of mTORC1 to address healthspan and a range of diseases of aging including metabolic, neurodegenerative, autoimmune diseases, certain cancers as well as age-related immune suppression and several genetic and rare diseases.
The discovery published in Science extends more than two decades of Sabatini’s research focused on the mTOR (mechanistic target of rapamycin) pathway, a critical regulator of cellular growth and metabolism. Previous discoveries published by the Sabatini laboratory in late 2014 found that a family of proteins called sestrins act as molecular sensors in the cell that regulate mTORC1 activity in response to the availability of amino acids. The newly published research in Science, which was performed in Sabatini’s laboratory at the Whitehead Institute for Biomedical Research, further elucidates that two members of the sestrin family directly bind to the amino acid leucine, which in turn regulates the activation status of mTORC1. The fact that dietary leucine levels dictate the availability of this essential amino acid and directly impact the physiological response mediated by mTORC1 places the sestrins at a critical regulatory node in the cell that can be pharmacologically modulated with small-molecule drug compounds to inhibit or activate the mTORC1 pathway.
Sabatini co-authored the paper in Science and serves as a Howard Hughes Medical Institute investigator, member of the Whitehead Institute, professor of biology at the Massachusetts Institute of Technology (MIT), member of the Koch Institute for Integrative Biology at MIT and associate member of the Broad Institute of Harvard and MIT.
“The discovery of this long sought-after mediator of mTORC1 activation by leucine opens up a novel and powerful approach to yield a new generation of drugs for multiple diseases of aging. This is exactly aligned with Navitor’s approach to develop medicines that selectively target mTORC1 based on targeting critical cellular proteins involved in the activation of mTORC1 through nutrients such as amino acids and other components,” said Dr. George P. Vlasuk, president and CEO of Navitor Pharmaceuticals.
“Leucine is one of the most physiologically important amino acids implicated in the regulation of mTORC1 activity; as such, it is a key driver of cellular growth and metabolism. This landmark discovery of the molecular sensor that links the availability of leucine to the activation status of mTORC1 in the cell facilitates a novel approach for the discovery and development of new drugs that can turn up or turn down mTORC1,” added Vlasuk.
The mTORC1 molecular complex integrates multiple cellular signaling pathways in response to the availability of nutrients such as amino acids, thereby serving as the primary central control point responsible for cellular growth and metabolism. The inhibition of mTORC1 has been demonstrated to address many diseases of aging—including metabolic, neurodegenerative, autoimmune diseases and certain cancers—as well as beneficially impacting healthspan and leading to improved longevity in species as diverse as yeast to mice. In contrast, the reduced activity of mTORC1 is thought to play an important role in the atrophy of skeletal muscle associated with age (sarcopenia), immobilization and disease. Therefore, targeting cellular components involved in the regulation of mTORC1 activity that can yield both “inhibitors” as well as “activators” of this complex offer a novel and potentially powerful approach to the discovery and development of a new generation of drugs for the treatment of many diseases caused by the dysregulation of mTORC1.
The discovery of the sestrin family of proteins as key mediators of cell growth (anabolism) through the direct regulation of mTORC1 activation in response to the amino acid leucine opens up a powerful new approach to regulating this important central component of cellular metabolism, says Vlasuk. “Navitor has developed specific biochemical and cellular assays that measure the activation of mTORC1 by sestrin proteins. These unique assays have been used to identify small-molecule compounds that specifically activate mTORC1 in cells and whole animal model systems. Targeting the sestrins has also resulted in the identification of selective inhibitors of mTORC1 activation, thereby making this single molecular target ideal for the discovery of new drug candidates that can turn-up or turn-down the activity of mTORC1. Specific small-molecule activators of mTORC1 are being developed at Navitor to treat atrophy that develops in skeletal muscle following prolonged immobilization due to injury or disease and eventually treating the age-dependent decline in muscle function or sarcopenia. Specific inhibitors of the pathway are being developed for a variety of diseases of aging caused by hyperactivation of mTORC1, including metabolic diseases such as type 2 diabetes and fatty liver disease and age-related decline in immune response (immunosenescence) as well as several rare diseases including tuberous sclerosis and lymphangioleiomyomatosis.”
The mTOR kinase exists in two multi-protein complexes within the cell, called mTORC1 and mTORC2. Both complexes are critical signaling nodes that regulate multiple cellular functions including metabolism, growth and response to changes in the cell’s environment. mTORC1 responds to and integrates the cell’s response to nutrient availability and growth factors and plays a key role in protein synthesis and cellular growth. As a critical regulatory pathway, mTORC1 is often dysregulated in multiple diseases across several important therapeutic areas. While several approved drugs (rapamycin and related allosteric mTORC1 inhibitors) target the broad mTOR pathway for certain specific disease applications, the use of these first-generation drugs has been limited since they inhibit both mTORC1 and mTORC2 leading to undesirable side effects when used chronically. Navitor’s therapeutics are designed to selectively modulate the cellular signals that are aberrant in disease processes caused by the dysregulation of mTORC1 activity without inhibiting mTORC2.
