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Targeting of non-canonical G protein signaling with small molecules

用小分子靶向非经典 G 蛋白信号传导

基本信息

批准号：
10180984
负责人：
Mikel Garcia-Marcos
金额：
$ 35.71万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10180984
关键词：
Achievement Affect Animal Cancer Model Area Behavioral Binding Biochemical Biochemistry Biological Biological Assay Biological Response Modifier Therapy Biophysics Breast Breast cancer metastasis Carcinoma Cell Communication Cells Cessation of life Chemicals Colon Computer Models Data Development Disease Disseminated Malignant Neoplasm Docking Evaluation FDA approved Functional disorder G-Protein-Coupled Receptors GTP-Binding Protein alpha Subunits, Gs GTP-Binding Proteins Goals Heterotrimeric GTP-Binding Proteins Intercellular Communication Process Investigation Lead Malignant Neoplasms Maps Mediating Membrane Metastatic Carcinoma Molecular Names Neoplasm Metastasis Nuclear Magnetic Resonance Patient-Focused Outcomes Permeability Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Physiological Physiology Pre-Clinical Model Process Prognosis Property Proteins Publishing Regulation Research Scanning Signal Transduction Signaling Protein Specificity Structure Structure-Activity Relationship Testing Therapeutic Therapeutic Effect Toxic effect Tumor Cell Migration Work base cell motility chemical synthesis cytotoxicity drug development experimental study high throughput screening human disease improved in vivo inhibitor/antagonist mouse model neoplastic cell novel novel therapeutics overexpression protein activation protein protein interaction response scaffold small molecule small molecule inhibitor tool tumor

项目摘要

The high importance of signaling via heterotrimeric G proteins in physiology and disease is reflected by the fact that G protein-coupled receptors (GPCRs), which activate G proteins, are the target for more that >25% of FDA-approved drugs. Interestingly, recent work by us and others has led to the identification a novel mechanism of trimeric G protein activation that is mediated by cytoplasmic, non-receptor proteins instead of membrane-bound GPCRs. Although this mechanism has important implications in human disease and targeting it is a novel opportunity to develop therapeutic approaches, it remains completely unexploited form a pharmacological standpoint. Our goal is to carry out proof-of- concept studies for early stage drug development of first-in-class small molecule inhibitors of a GPCR- independent mechanism of G protein activation that promotes cancer metastasis. More specifically, our efforts will be focused on developing and characterizing small molecules that disrupt the protein-protein interaction (PPI) formed between the G protein Gαi and its non-receptor activator GIV (aka Girdin). Many independent studies have demonstrated that GIV is upregulated in metastatic carcinomas. Upon GIV overexpression, the GIV-Gαi PPI enhances signaling responses that lead to increased tumor cell migration and invasion. Thus, inhibition of the GIV-Gαi PPI is a vulnerability of metastatic tumor cells that might provide a therapeutic window to treat aggressive metastatic cancers. This is of paramount significance because metastasis is the cause of >90% of cancer related deaths and there are very limited therapeutic options for it. PRELIMINARY DATA AND EXPERIMENTAL PLAN: In recently published work, we have characterized the structure of the GIV-Gαi interface and demonstrated that it can be disrupted by small molecules. We have subsequently performed a screen of 200,000 compounds. We confirmed hits identified in the primary screen with an orthogonal biochemical assay, filtered out compounds with chemical liabilities and validated them analytically after re-purchase/re-synthesis. After evaluation in biological assays, we have identified small molecules based on four unrelated, synthetically tractable scaffolds that disrupt the GIV-Gαi PPI with IC50's in the ~0.5-30 µM range and that display the expected biological activity of blocking tumor cell migration without undesired non-specific toxicity. We hypothesize that these compounds selectively disrupt the GIV-Gαi PPI to block the signaling and cell behavioral processes by which this PPI drives tumor invasiveness, and that upon optimization, these compounds will have therapeutic effects in pre-clinical models of metastasis. In Aim 1 we will comprehensively characterize the mode of action of the newly identified inhibitors using biochemical, biophysical and cell-based approaches, while in Aim 2 we will optimize the most promising of our compounds to increase its potency and druglike properties to achieve therapeutic effects in mouse models of metastasis.

通过异源三聚体 G 蛋白进行信号传导的高度重要性 G 蛋白偶联受体 (GPCR) 激活 G 蛋白，反映了生理学和疾病的情况。蛋白质是超过 25% FDA 批准药物的目标。有趣的是，我们和其他人最近的工作导致鉴定出一种由细胞质介导的三聚体 G 蛋白激活的新机制，非受体蛋白代替膜结合 GPCR。尽管这一机制具有重要意义对人类疾病的影响并针对它是开发治疗方法的新机会，它从药理学的角度来看，它仍然完全未被开发。我们的目标是进行证明- 一流的 GPCR 小分子抑制剂的早期药物开发概念研究 G蛋白激活促进癌症转移的独立机制。更具体地说，我们的工作重点是开发和表征破坏蛋白质-蛋白质的小分子 G 蛋白 Gαi 与其非受体激活剂 GIV（又名 Girdin）之间形成相互作用（PPI）。许多独立研究表明 GIV 在转移性癌中表达上调。在 GIV 上过表达时，GIV-Gαi PPI 增强信号反应，导致肿瘤细胞迁移增加，入侵。因此，抑制 GIV-Gαi PPI 是转移性肿瘤细胞的一个弱点，可能会提供一种治疗侵袭性转移性癌症的治疗窗口。这是至关重要的，因为转移是 90% 以上的癌症相关死亡的原因，并且其治疗选择非常有限。初步数据和实验计划：在最近发表的工作中，我们描述了 GIV-Gαi 界面的结构并证明它可以被小分子破坏。我们有随后对 200,000 种化合物进行了筛选。我们确认了主屏幕中识别的点击通过正交生化测定，过滤出具有化学倾向的化合物并对其进行验证重新购买/重新合成后进行分析。经过生物测定评估后，我们发现了一些小基于四种不相关的、合成上易于处理的支架的分子，这些支架可破坏 GIV-Gαi PPI，IC50 值在 ~0.5-30 µM 范围，并且显示出阻止肿瘤细胞迁移的预期生物活性，而无需不良的非特异性毒性。我们假设这些化合物选择性地破坏 GIV-Gαi PPI 阻断 PPI 驱动肿瘤侵袭的信号传导和细胞行为过程，并且经过优化，这些化合物将在临床前转移模型中具有治疗作用。在目标 1 中，我们将利用生化全面表征新发现的抑制剂的作用模式，生物物理和基于细胞的方法，而在目标 2 中，我们将优化最有前途的化合物增加其效力和类药特性，以在小鼠转移模型中达到治疗效果。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Small-molecule targeting of GPCR-independent non-canonical G protein signaling inhibits cancer progression.

小分子靶向不依赖于 GPCR 的非经典 G 蛋白信号传导可抑制癌症进展。

DOI：
10.1101/2023.02.18.529092
发表时间：
2023
期刊：
bioRxiv : the preprint server for biology
影响因子：
0
作者：
Zhao,Jingyi;DiGiacomo,Vincent;Ferreras-Gutierrez,Mariola;Dastjerdi,Shiva;deOpakua,AlainIbáñez;Park,Jong-Chan;Luebbers,Alex;Chen,Qingyan;Beeler,Aaron;Blanco,FranciscoJ;Garcia-Marcos,Mikel
通讯作者：
Garcia-Marcos,Mikel

Small-molecule targeting of GPCR-independent noncanonical G-protein signaling in cancer.