Series of discoveries of new nutrient sensors opens opportunities for drug targets that selectively regulate mTORC1 in a range of disease pathways
CAMBRIDGE, Mass. – November 9, 2017 – Navitor Pharmaceuticals, Inc., a biopharmaceutical company developing novel medicines specifically targeting the activation of mTORC1, today announced a publication by the company’s scientific founder, David M. Sabatini, M.D., Ph.D., whose groundbreaking research has identified and characterized several new cellular proteins, called nutrient sensors, that are key ‘switches’ [or mediators] for regulating mTORC1 activity. Today, Dr. Sabatini published in the journal Science the discovery of a new nutrient sensor in the mTORC1 pathway, SAMTOR; this follows a series of previous publications from Sabatini’s lab about other newly-discovered nutrient sensors that regulate the activation of mTORC1 by amino acids. These nutrient sensors represent a new avenue for developing novel drugs that can selectively regulate mTORC1 which is an important pathway in a range of diseases. The newly‐published research in Science was performed in Dr. Sabatini’s laboratory at the Whitehead Institute for Biomedical Research. Dr. Sabatini is an Investigator of the Howard Hughes Medical Institute, Member of Whitehead Institute for Biomedical Research, and Professor of Biology at the Massachusetts Institute of Technology.
“These publications are important new contributions by Dr. Sabatini to an increasingly more robust picture of the molecular mechanisms that regulate mTORC1 activity and provide new insights into therapeutic targets to treat a range of diseases including neurological and fibrotic diseases, rare diseases and immunometabolism,” said George P. Vlasuk, Ph.D., President and CEO of Navitor Pharmaceuticals.”
The paper published in Science describes for the first time SAMTOR, a previously uncharacterized protein that inhibits mTORC1 signaling based upon availability of S-adenosylmethionine (SAM), an important metabolite of the amino acid methionine which has been associated with improved insulin sensitivity and extended lifespan in rodents. Another recent paper published last month in the journal Cell describes the function of SLC38A9, a protein found in the membrane of lysosomes, intracellular organelles responsible for protein degradation. SLC38A9, the first described lysosomal-associated nutrient sensor, regulates cellular growth through mTORC1 in response to the availability of the amino acid arginine within that compartment.
Together, these discoveries of new nutrient sensors reveal a new understanding of the complex regulatory pathways that determine mTORC1 activity. Publications from Dr. Sabatini’s lab have identified and characterized several amino acid sensors that regulate mTORC1 signaling, including:
- Sestrin1 and Sestrin2 as nutrient sensors for leucine availability within the cell;
- SLC38A9 as an arginine-dependent nutrient sensor for leucine availability in the lysosome;
- CASTOR1 as a nutrient sensor for arginine within the cell; and
- SAMTOR as a nutrient sensor for SAM, a methionine metabolite, within the cell.
“The on-going discoveries into the molecular mechanisms that regulate mTORC1 activity provide new opportunities to intervene in this critically important pathway,” said Dr. Vlasuk. “We are translating these seminal molecular insights about nutrient sensors into a pipeline of drugs that are designed to turn up or turn down mTORC1 activity to treat disease.”
The mTOR (mechanistic target of rapamycin) 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, energy and certain 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.
About Nutrient Sensors for Modulating mTORC1 Activity
Nutrient sensors are specialized, intracellular proteins expressed in a cell to enable it to sense and respond to the availability of amino acids, glucose, and other biomolecules and direct normal cell function. In different tissues the availabilities of certain amino acids – the building blocks of proteins – initiate cellular processes by regulating mTORC1 activity to maintain homeostasis. The amino acid sensors Sestrin2 and CASTOR have been shown to direct mTORC1 activity based upon availabilities of the amino acids leucine and arginine, respectively. These findings provide a mechanism to unlock the therapeutic potential of mTOR and restore normal mTORC1 activity to treat diseases caused by dysfunctional mTORC1 activity.
Navitor Pharmaceuticals, Inc., is a biopharmaceutical company discovering and developing novel medicines that target the nutrient sensing pathways that regulate mTORC1, a master regulator of cellular growth and metabolism. The company’s proprietary drug discovery platform unlocks the therapeutic potential of mTOR by bringing together deep knowledge into nutrient sensors, proprietary biological tools and expertise regarding the correlation of mTORC1 activity in disease. Navitor’s small molecule therapeutics are designed to selectively modulate the cellular signals that are aberrant in disease processes caused by the dysregulation of mTORC1 activation to address a wide range of diseases, including neurological and fibrotic disorders, immunometabolism and certain rare diseases. The company’s founding intellectual property includes exclusive rights to groundbreaking discoveries related to the mTORC1 pathway and nutrient signaling mechanisms by Dr. David Sabatini at The Whitehead Institute for Biomedical Research however, the research leading to these discoveries is not funded by Navitor. The company is backed by leading financial and corporate investors, including Polaris Partners, Atlas Venture, Johnson & Johnson Innovation – JJDC, Inc., SR One, Ltd., Brace Pharma Capital, Remeditex Ventures and Sanofi Ventures. For more information, please visit www.navitorpharma.com