# Targeting the GTP-bound state of oncogenic Ras proteins

> **NIH NIH F32** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2021 · $68,562

## Abstract

RESEARCH SUMMARY/ABSTRACT
 Mutations in Ras genes are the most common activators of cancer in humans, and effective inhibitors of the
GTPases they encode have been sought as potential cancer therapeutics. Despite extensive research in this
field, Ras proteins remain among the most challenging targets in medical chemistry. Oncogenic mutations in
Ras genes typically result in proteins locked in the “on” GTP-bound state, which binds its effectors Raf kinases
and PI3K. Therefore, small molecules that target GTP-bound Ras proteins and disrupt interactions with effectors
are expected to be promising cancer therapeutics. This proposal seeks to develop small molecule inhibitors of
Ras(GTP) by targeting the recently discovered “switch II groove.” The strategy combines techniques from
synthetic chemistry, combinatorial chemistry, and chemical biology to increase the non-covalent affinity of
binders, evaluate them as inhibitors of Ras(GTP), and develop N- and H-Ras oncogene-selective inhibitors.
 This research strategy was designed to both leverage my existing knowledge of synthetic chemistry and train
me in new chemical biology techniques. The experimental work will require me to learn protein expression and
purification, protein NMR spectroscopy, and a range of biochemical assays to detect inhibition of Ras GTPases.
By reading the relevant literature and discussing this project with experienced scientists, I will greatly improve
my understanding of the protein signaling pathways involved in cell growth and proliferation which are mis-
regulated in cancer. UCSF is an ideal location for me to receive training in chemical biology due to its wide range
of experienced faculty, excellent instrumentation facilities, and connections with the wider chemical biology
community.
 I intend to pursue an academic career applying organic chemistry to the improvement of human health;
specifically, I wish to develop new synthetic methodology to enable the discovery of inhibitors for challenging
and dynamic protein targets. My academic studies and graduate research have given me a strong background
in organic chemistry and synthetic methods; however, my formal training in chemical biology is lacking. I chose
to join Professor Shokat’s group at UCSF because I believe he is an ideal mentor to help me remedy that lack
and better prepare me for an independent career.

## Key facts

- **NIH application ID:** 10213636
- **Project number:** 5F32CA253966-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** David Matthew Peacock
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $68,562
- **Award type:** 5
- **Project period:** 2020-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10213636

## Citation

> US National Institutes of Health, RePORTER application 10213636, Targeting the GTP-bound state of oncogenic Ras proteins (5F32CA253966-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10213636. Licensed CC0.

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