# Inhibition of mTOR by a small molecule activator of TSC2

> **NIH NIH R21** · BRANDEIS UNIVERSITY · 2020 · $242,562

## Abstract

The mechanistic target of rapamycin complex 1 (mTORC1) is a master regulator of
cell growth. Commensurate with mTORC1's importance, a complex network of growth
factor signaling and nutrient sensing pathways regulate mTORC1 activity, which in turn
regulates protein synthesis and many other cellular processes. Hyperactivation of
mTORC1 signaling is a common feature of the diseases and conditions of aging.
mTORC1 inhibition is a promising treatment strategy for these diseases. mTORC1
inhibitors increase improve prevent cancer, decrease obesity and reverse age-related
immune decline in humans and display activity in rodent models of neurodegeneration,
cardiomyopathy, atheroscelerosis, retinopathy and hearing loss. mTORC1 inhibitors
also increase lifespan in mice, worms and yeast. We have discovered a small molecule
(CB3A) that inhibits mTORC1 signaling via a novel mechanism. Unlike other small
molecule inhibitors of mTORC1, CB3A preferentially decreases the phosphorylation of
4EBP1 relative to S6K. Thus CB3A-inspired drugs may provide a therapeutic benefit for
diseases/conditions where 4EBP1 phosphorylation is the driver. These
diseases/conditions include cancer, diabetes and muscle loss. However, mTORC1
hyperactivation can derive from diverse underlying molecular mechanisms. Therefore
the goal of this project is to elucidate the mechanism of CB3A action. This information
is required to identify which diseases are most likely to respond to a CB3A-inspired
treatment strategy. Our preliminary results show that CB3A increases the ubiquitination
of the negative mTORC1 regulator TSC2. Although the regulation of TSC2 by
phosphorylation is well recognized, little is known about the role of ubiquitination in
TSC2/mTORC1 regulation. CB3A itself is unlikely to have therapeutic value, but
understanding the mechanism of CB3A inhibition is likely to identify new potential
targets as well as new facets of mTORC1 regulation.

## Key facts

- **NIH application ID:** 9976416
- **Project number:** 5R21AG061640-02
- **Recipient organization:** BRANDEIS UNIVERSITY
- **Principal Investigator:** Lizbeth K. Hedstrom
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $242,562
- **Award type:** 5
- **Project period:** 2019-07-15 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9976416

## Citation

> US National Institutes of Health, RePORTER application 9976416, Inhibition of mTOR by a small molecule activator of TSC2 (5R21AG061640-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9976416. Licensed CC0.

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