# Selectively Targeting Oncogenic NRAS in Cancer

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2021 · $531,791

## Abstract

SPECIFIC AIMS
Oncogenic RAS mutations, which are among the most common molecular alterations in cancer, encode
mutant proteins that dominantly drive aberrant growth. Unfortunately, structural and biochemical properties of
the mutant Ras/GTPase activating protein (Ras/GAP) molecular switch pose formidable barriers to
mechanism-based drug discovery and no targeted therapies have been approved for Ras-driven cancers to
date. The Ras palmitoylation/depalmitoylation cycle regulates the subcellular trafficking of the N-Ras, H-Ras,
and K-Ras4a isoforms, but not of K-Ras4b. Thus, developing potent and selective inhibitors of the Ras
palmitoylation/depalmitoylation cycle has the potential to treat malignancies dependent on oncogenic N-Ras
without interfering with K-Ras4b signaling in normal tissues. This ongoing project involves a cross-disciplinary
collaboration between investigators with complementery expertise in biochemistry, chemical biology,
hematologic cancer, Ras signaling, and preclinical therapeutics. During the current funding period we: (1)
validated N-Ras palmitoylation as a promising therapeutic target for NRAS mutant cancers in a novel strain of
NrasG12D,C181S “knock in” mice; (2) identified the ABHD17 family of serine hydrolase (SH) enzymes as N-Ras
depalmitoylases; (3) showed that the Palmostatin class of SH inhibitors are too promiscuous for use as
selective probes of ABHD17 function; (4) identified, in collaboration with Lundbeck, a structurally distinct class
of selective ABHD17 inhibitors that reduce the growth of NRAS mutant acute myeloid leukemia (AML) cells
and exhibit genotype-specific activity in isogenic models; and, (5) demonstrated that reduced growth of NRAS
mutant AML cells treated with ABHD17 inhibigtors correlates with biochemical inhibition of Ras effector
pathways. The experiments proposed in this renewal application will extend these exciting studies through the
following specific aims: Aim 1. To investigate the roles of ABHD17s and additional SH enzymes in N-Ras
depalmitoylation and to test the potent and bioavailable ABHD17 inhibitor ABD778 in preclinical models of
AML; and, Aim 2. To identify palmitoyl acyl transferase (PAT) proteins that modify N-Ras and to validate them
as targets for N-Ras mutant cancers. We anticipate that the studies described in this interdisciplinary project
will determine fundamental mechanisms of N-Ras palmitoylation, ascertain the efficacy and mechanism of
action of chemical inhibitors of ABHD17s alone and in combination with other targeted agents, and generate
essential foundational knowledge for developing PAT inhibitors as anti-cancer drugs. The development of
selective inhibitors of oncogenic N-Ras signaling would have significant therapeutic impact for a number of
different aggressive adult and pediatric cancers.

## Key facts

- **NIH application ID:** 10209682
- **Project number:** 2R01CA193994-06A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** KEVIN M. SHANNON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $531,791
- **Award type:** 2
- **Project period:** 2015-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10209682

## Citation

> US National Institutes of Health, RePORTER application 10209682, Selectively Targeting Oncogenic NRAS in Cancer (2R01CA193994-06A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10209682. Licensed CC0.

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