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:
- 金额:$ 35.71万
- 依托单位:
- 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:
- 关键词:AchievementAffectAnimal Cancer ModelAreaBehavioralBindingBiochemicalBiochemistryBiologicalBiological AssayBiological Response Modifier TherapyBiophysicsBreastBreast cancer metastasisCarcinomaCell CommunicationCellsCessation of lifeChemicalsColonComputer ModelsDataDevelopmentDiseaseDisseminated Malignant NeoplasmDockingEvaluationFDA approvedFunctional disorderG-Protein-Coupled ReceptorsGTP-Binding Protein alpha Subunits, GsGTP-Binding ProteinsGoalsHeterotrimeric GTP-Binding ProteinsIntercellular Communication ProcessInvestigationLeadMalignant NeoplasmsMapsMediatingMembraneMetastatic CarcinomaMolecularNamesNeoplasm MetastasisNuclear Magnetic ResonancePatient-Focused OutcomesPermeabilityPharmaceutical ChemistryPharmaceutical PreparationsPharmacologyPhysiologicalPhysiologyPre-Clinical ModelProcessPrognosisPropertyProteinsPublishingRegulationResearchScanningSignal TransductionSignaling ProteinSpecificityStructureStructure-Activity RelationshipTestingTherapeuticTherapeutic EffectToxic effectTumor Cell MigrationWorkbasecell motilitychemical synthesiscytotoxicitydrug developmentexperimental studyhigh throughput screeninghuman diseaseimprovedin vivoinhibitor/antagonistmouse modelneoplastic cellnovelnovel therapeuticsoverexpressionprotein activationprotein protein interactionresponsescaffoldsmall moleculesmall molecule inhibitortooltumor
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:
- 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.
- DOI:10.1073/pnas.2213140120
- 发表时间:2023-05-02
- 期刊:
- 影响因子:11.1
- 作者:
- 通讯作者:
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Mikel Garcia-Marcos其他文献
Mikel Garcia-Marcos的其他文献
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{{ truncateString('Mikel Garcia-Marcos', 18)}}的其他基金
Versatile and high-fidelity optical biosensor platforms for GPCR signaling
用于 GPCR 信号传导的多功能高保真光学生物传感器平台
- 批准号:
10679863 - 财政年份:2023
- 资助金额:
$ 35.71万 - 项目类别:
Direct chemogenetic control of heterotrimeric G protein signaling
异源三聚体 G 蛋白信号传导的直接化学遗传学控制
- 批准号:
10590217 - 财政年份:2022
- 资助金额:
$ 35.71万 - 项目类别:
Non-canonical activation of heterotrimeric G protein signaling in vivo
异源三聚体 G 蛋白信号传导的体内非典型激活
- 批准号:
10220082 - 财政年份:2019
- 资助金额:
$ 35.71万 - 项目类别:
Non-canonical activation of heterotrimeric G protein signaling in vivo
异源三聚体 G 蛋白信号传导的体内非典型激活
- 批准号:
10461747 - 财政年份:2019
- 资助金额:
$ 35.71万 - 项目类别:
Non-canonical activation of heterotrimeric G protein signaling in vivo
异源三聚体 G 蛋白信号传导的体内非典型激活
- 批准号:
9914590 - 财政年份:2019
- 资助金额:
$ 35.71万 - 项目类别:
Non-canonical activation of heterotrimeric G protein signaling in vivo
异源三聚体 G 蛋白信号传导的体内非典型激活
- 批准号:
10018921 - 财政年份:2019
- 资助金额:
$ 35.71万 - 项目类别:
Non-canonical activation of heterotrimeric G protein signaling in vivo
异源三聚体 G 蛋白信号传导的体内非典型激活
- 批准号:
10581960 - 财政年份:2019
- 资助金额:
$ 35.71万 - 项目类别:
Next generation G protein activity biosensors
下一代 G 蛋白活性生物传感器
- 批准号:
9789949 - 财政年份:2018
- 资助金额:
$ 35.71万 - 项目类别:
Identification of chemical probes that specifically disrupt the GIV-Gi interface
鉴定特异性破坏 GIV-Gi 界面的化学探针
- 批准号:
8986801 - 财政年份:2015
- 资助金额:
$ 35.71万 - 项目类别:
Alternative mechanisms of signaling via trimeric G proteins
通过三聚体 G 蛋白传递信号的替代机制
- 批准号:
10374905 - 财政年份:2014
- 资助金额:
$ 35.71万 - 项目类别:
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