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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：
10579287
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/10579287
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 Learning Lesion Ligands MEKs Malignant Neoplasms Malignant neoplasm of pancreas Measures Mediating Messenger RNA Methods Modeling Molecular Molecular Conformation Mucinous Neoplasm Mutate Mutation 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 peptide natural products 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.

驱动胰腺肿瘤发生的 G 蛋白 Gαs 抑制剂项目概要/摘要 GNAS 基因编码异源三聚体 G 蛋白的 Gαs 刺激亚基，介导 G 蛋白偶联受体（GPCR）信号传导，细胞感知和响应细胞外刺激的核心机制。多种人类癌症类型在该通路中表现出反复出现的功能获得性突变，最常见的是针对 GNAS。 GNAS 经常发生突变的最致命的肿瘤类型是导管内乳头状肿瘤粘液性肿瘤（IPMN），浸润性胰腺癌的前兆。 Bardeesy 最近的小鼠模型和同事已经证明，胰腺 IPMN 肿瘤包含三个一致的遗传病变，K-Ras (G12D)、Gαs (R201C) 和 p53 -/- 在 Gαs (R201C) 沉默时受到抑制，从而提供强大的遗传性验证针对该突变蛋白。 30 多年来，解释增益的流行模型是 R201 突变的功能活性是通过 GTPase 活性的丧失并导致突变体丧失能力而实现的。 Gαs 切换至 GDP 状态。最近，我们实验室对此模型进行了修改，发现R201C 突变可以通过稳定 GTP 直接激活 GDP 结合的 Gα 来绕过 GTP 结合的需要。分子内氢键网络。这种理解带来了我们寻求的治疗机会利用治疗胰腺肿瘤发生。我们建议开发状态选择性 Gαs 结合分子阻断腺苷酸环化酶 (AC) 激活。受到环肽天然产物 YM-254890 的启发，它是一种 Gαq 的 GDP 状态特异性环肽抑制剂，我们启动了药物发现方法来识别这两种活性 Gαs 状态和非活性状态特异性抑制剂。使用随机非标准肽集成发现 (RaPID) 系统由我们的合作者 Hiroaki Suga 博士开发，我们选择了活动状态和非活动状态相对于 Gαs，更喜欢环肽。我们已经解决了我们功能的高分辨率 X 射线共晶结构阻断环肽解释了它们的核苷酸状态特异性和抑制活性。我们建议使用 RaPID 技术关注化学多样性，以提高先导环肽的效力并测试我们的 Bardeesy 博士的模型生成的细胞中的先导分子。该提案利用了最近的三个突破、Bardeesy 博士的小鼠建模、Suga 博士的非天然环肽库生成以及我们的实验室通过驱动癌蛋白 Gαs 发出新的非规范类型 G 蛋白信号，以针对致命的胰腺癌的一种形式。