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.

G蛋白Gαs的抑制剂，驱动胰腺肿瘤发生项目摘要 /摘要 GNA基因编码异三聚体G蛋白的GαS刺激亚基，该亚蛋白介导G蛋白 - 耦合受体（GPCR）信号传导，这是一种中心机制，细胞感知并响应细胞外刺激。多种人类癌症类型在途径中暴露了复发性获得突变，最常靶向GNA。 GNA经常突变的最致命的肿瘤类型是导管内乳头状粘液性肿瘤（IPMN），浸润性胰腺癌的前体。 Bardeesy最近的鼠标建模同事表明，胰腺IPMN肿瘤包含三个一致的遗传病变，K-RAS 当GαS（R201C）沉默时，（G12D），GαS（R201C）和p53 - / - 被抑制，提供强遗传靶向该突变蛋白的验证。 30多年来，流行的模型解释了 - R201突变的功能活性是通过GTPase活性的丧失和突变体的无能为力 GαS关闭到GDP状态。最近，我们的实验室修改了该模型，并揭示了R201C 突变可以通过稳定稳定GDP结合的GTP结合的需求分子内氢键网络。这种理解导致了我们寻求的治疗机会利用以治疗胰腺肿瘤发生。我们建议开发状态选择性的Gαs结合分子，这些分子阻断腺苷酸环化酶（AC）激活。受环状肽天然产品YM-254890的启发 GDP状态特异性环状肽抑制剂GαQ，我们启动了一种药物发现方法来识别这两种活动状态和无活性状态特异性抑制剂。使用随机的非标准肽集成发现（快速）由我们的合作者Hiroaki Suga博士开发的系统，我们选择了活跃状态和不活跃状态偏爱环状肽而不是Gα。我们已经解决了我们功能的高分辨率X射线共结晶结构阻止循环宠物解释其核丁基状态的特异性和抑制活性。我们建议利用快速技术将化学多样性集中在提高铅环的效力并测试我们的由Bardeesy博士模型产生的细胞中的铅分子。该提案大写了最近的三个突破，Bardeesy博士的鼠标建模，Suga博士的不自然环状肽库的生成和A 我们实验室的驱动蛋白Gα的新型非典型的G蛋白信号传导针对致命胰腺癌的形式。