# A Chemical-Genetic Platform for Interrogating Specific mTOR Functions

> **NIH NIH F31** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2021 · $37,796

## Abstract

Project Summary / Abstract
Mechanistic Target of Rapamycin (mTOR) is a protein kinase that acts through two distinct
protein complexes to control critical cellular processes including protein synthesis, autophagy,
and cell motility. Hyperactivation of mTOR drives oncogenesis through increases in cell growth
and survival. In recent years, new pharmacological tools have helped make sense of the
intricate mTOR signaling network, revealing the necessity of certain downstream mTOR
effectors in cancerous tissue and the importance of mTOR complex 2 (mTORC2) as a
therapeutic target. The goal of this proposal is to develop chemical-genetic tools for studying
specific aspects of mTOR signaling. In particular, we propose to develop a method by which we
can specifically inhibit mTORC2 to study its role in cancer. Currently there are no
pharmacological inhibitors specific to mTORC2. Genetic methods for inhibiting mTORC2 require
knockout or knockdown of genes encoding proteins in mTORC2. This approach disrupts the
balance between the two mTOR complexes and suffers from slow onset, leading to the
activation of complex feedback networks. In Aim 1, we propose to develop a small molecule that
inhibits mTOR if and only if an auxiliary protein is present. This system would allow us to
express the auxiliary protein in a specific cell type or even subcellular compartment, thereby
sensitizing mTOR to small molecule inhibition in only those cells or compartments. This
approach has several advantages; namely, it functions through a gain-of-function mechanism
where an inert auxiliary protein is introduced, leaving the endogenous system intact and
unchanged until the small molecule inhibitor is introduced. Preliminary data show that we have
successfully identified a small molecule that selectively inhibits mTOR in yeast or mammalian
cells exogenously expressing an auxiliary protein. In Aim 2, we propose to apply this tool to
specifically inhibit mTORC2 and study how it contributes to cell growth and survival in cancer.
We hypothesize that phosphorylation of particular mTORC2 substrates is critical for tumor
growth and survival, and these substrates can be revealed using specific mTORC2 inhibitors.
Completion of this proposal will provide a new chemical-genetic tool to address a previously
unmet need in the area of mTOR biology: the ability to selectively inhibit subpopulations of
mTOR. This will shed light on the critical roles of mTOR dysregulation in cancer and provide
novel therapeutic strategies.

## Key facts

- **NIH application ID:** 10200712
- **Project number:** 5F31CA243439-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Douglas Ryan Wassarman
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $37,796
- **Award type:** 5
- **Project period:** 2019-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10200712

## Citation

> US National Institutes of Health, RePORTER application 10200712, A Chemical-Genetic Platform for Interrogating Specific mTOR Functions (5F31CA243439-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10200712. Licensed CC0.

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