权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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蛋白传递信号的高度重要性

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.