# Inhibitors of the G protein GNAS which drives pancreatic tumorigenesis

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2023 · $395,637

## Abstract

Inhibitors of the G protein Gαs which drives pancreatic tumorigenesis
Project Summary / Abstract
The GNAS gene encodes the Gαs stimulatory subunit of heterotrimeric G proteins, which mediate G-protein-
coupled receptor (GPCR) signaling, a central mechanism by which cells sense and respond to extracellular stimuli.
Multiple human cancer types exhibit recurrent gain-of-function mutations in the pathway, most frequently
targeting GNAS. The most lethal tumor type where GNAS is frequently mutated is the intraductal papillary
mucinous neoplasms (IPMN), a precursor of invasive pancreatic cancer. Recent mouse modelling from Bardeesy
and coworkers has shown that pancreatic IPMN tumors which contain three coincident genetic lesions, K-Ras
(G12D), Gαs (R201C), and p53 -/-, are suppressed when Gαs (R201C) is silenced, providing strong genetic
validation for targeting this mutant protein. For over 30 years, the prevailing model explaining the gain-of-
function activity of the R201 mutations was through the loss of GTPase activity and resulting inability of mutant
Gαs to switch off to the GDP state. Recently, our laboratory revised this model and revealed that the R201C
mutation can bypass the need for GTP binding by directly activating GDP-bound Gαs through stabilization of an
intramolecular hydrogen bond network. This understanding has led to a therapeutic opportunity that we seek to
exploit to treat pancreatic tumorigenesis. We propose to develop state-selective Gαs binding molecules which
block adenylyl cyclase (AC) activation. Inspired by the cyclic peptide natural product YM-254890 which is a
GDP-state specific cyclic peptide inhibitor of Gαq, we initiated a drug discovery approach to identify both active
state and inactive state specific inhibitors of Gαs. Using the Random non-standard Peptide Integrated Discovery
(RaPID) system developed by our collaborator Dr. Hiroaki Suga we have selected active state and inactive state
preferring cyclic peptides against Gαs. We have solved high resolution X-ray co-crystal structures of our function
blocking cyclic peptides which explain their nucleotide state specificity and inhibitory activity. We propose to
use the RaPID technology to focus chemical diversity to improve potency of the lead cyclic peptides and test our
lead molecules in cells generated from Dr. Bardeesy's model. This proposal capitalizes on three recent
breakthroughs, mouse modeling by Dr. Bardeesy, unnatural cyclic peptide library generation by Dr. Suga, and a
new non-canonical type of G protein signaling by the driver oncoprotein Gαs by our laboratory to target a deadly
form of pancreatic cancer.

## Key facts

- **NIH application ID:** 10579287
- **Project number:** 5R01CA244550-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** KEVAN M. SHOKAT
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $395,637
- **Award type:** 5
- **Project period:** 2020-03-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10579287

## Citation

> US National Institutes of Health, RePORTER application 10579287, Inhibitors of the G protein GNAS which drives pancreatic tumorigenesis (5R01CA244550-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10579287. Licensed CC0.

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