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Inhibitors of the G protein GNAS which drives pancreatic tumorigenesis

驱动胰腺肿瘤发生的 G 蛋白 GNAS 抑制剂

基本信息

批准号：
10355430
负责人：
KEVAN M. SHOKAT
金额：
$ 39.56万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10355430
关键词：
Adenylate Cyclase Adopted Affinity Binding Biological Assay Bypass Cancer Etiology Cell model Cells Chemicals Complex Crystallization Cyclic Peptides Data Drops Drug Design Evaluation Exhibits G Protein-Coupled Receptor Signaling GNAS gene GTP Binding GTP-Binding Protein alpha Subunits, Gs GTP-Binding Proteins Gases Generations Genetic Gnas protein Guanosine Triphosphate Phosphohydrolases Heterotrimeric G Protein Subunit Human Hydrogen Bonding KRAS2 gene KRASG12D Laboratories Lead Lesion Ligands MEKs Malignant Neoplasms Malignant neoplasm of pancreas Measures Mediating Messenger RNA Methods Modeling Molecular Molecular Conformation Mucinous Neoplasm Mutate Mutation Natural Products Nucleotides Oncogenic Oncoproteins Pancreas Papillary Pathway interactions Penetration Peptide Library Peptides Permeability Proteins Recurrence Research Resolution Roentgen Rays Signal Transduction Signaling Protein Specificity Stimulus Structure System TP53 gene Technology Testing Therapeutic Tumor-Derived United States Validation Variant Woman cancer type cell growth driver mutation drug discovery extracellular gain of function gain of function mutation improved in vitro Assay inhibitor kinase inhibitor men mouse model mutant novel therapeutics pancreatic cancer cells pancreatic cancer patients pancreatic neoplasm pancreatic tumorigenesis protein complex targeted treatment three dimensional structure tumor

项目摘要

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.

抑制胰腺肿瘤发生的G蛋白Gαs