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蛋白的信号传导在
生理学和疾病的反应是由G蛋白偶联受体(GPCR),激活G蛋白偶联受体(GPCR),
蛋白质是超过25%的FDA批准药物的靶点。有趣的是,我们和其他人最近的工作
已经导致鉴定了三聚体G蛋白激活的新机制,
非受体蛋白而不是膜结合的GPCR。虽然这一机制具有重要的
在人类疾病中的意义和靶向它是一个新的机会,开发治疗方法,它
从药理学的角度来看仍然完全未被开发。我们的目标是进行验证-
用于GPCR的一流小分子抑制剂的早期药物开发的概念研究-
G蛋白激活促进癌症转移的独立机制。更具体地说,我们的
将集中精力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)之间形成的相互作用(PPI)。许多
独立的研究已经证明GIV在转移性癌中上调。关于GIV
过表达,GIV-Gαi PPI增强信号传导反应,导致肿瘤细胞迁移增加,
入侵因此,GIV-Gαi PPI的抑制是转移性肿瘤细胞的脆弱性,这可能提供了一种治疗方法。
治疗侵袭性转移性癌症的治疗窗口。这一点至关重要,因为
转移是>90%的癌症相关死亡的原因,并且其治疗选择非常有限。
初步数据和实验数据: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
随后进行了200,000种化合物的筛选。我们确认了在主屏幕上识别的匹配
通过正交试验筛选出化学成分不稳定的化合物,并对其进行验证
重新购买/重新合成后进行分析。在生物测定中评估后,我们已经鉴定了小的
分子基于四个不相关的,合成易处理的支架,破坏GIV-Gαi PPI,IC 50为
在~0.5-30 μM范围内,显示出预期的阻断肿瘤细胞迁移的生物活性,
不希望的非特异性毒性。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,
通过优化,这些化合物将在转移的临床前模型中具有治疗效果。在目标1中,
将使用生物化学,
生物物理和基于细胞的方法,而在目标2中,我们将优化我们最有前途的化合物
以增加其效力和类药性,从而在转移的小鼠模型中实现治疗效果。
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:
- 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:
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Mikel Garcia-Marcos其他文献
Mikel Garcia-Marcos的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ 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:
相似海外基金
How Does Particle Material Properties Insoluble and Partially Soluble Affect Sensory Perception Of Fat based Products
不溶性和部分可溶的颗粒材料特性如何影响脂肪基产品的感官知觉
- 批准号:
BB/Z514391/1 - 财政年份:2024
- 资助金额:
$ 35.71万 - 项目类别:
Training Grant
BRC-BIO: Establishing Astrangia poculata as a study system to understand how multi-partner symbiotic interactions affect pathogen response in cnidarians
BRC-BIO:建立 Astrangia poculata 作为研究系统,以了解多伙伴共生相互作用如何影响刺胞动物的病原体反应
- 批准号:
2312555 - 财政年份:2024
- 资助金额:
$ 35.71万 - 项目类别:
Standard Grant
RII Track-4:NSF: From the Ground Up to the Air Above Coastal Dunes: How Groundwater and Evaporation Affect the Mechanism of Wind Erosion
RII Track-4:NSF:从地面到沿海沙丘上方的空气:地下水和蒸发如何影响风蚀机制
- 批准号:
2327346 - 财政年份:2024
- 资助金额:
$ 35.71万 - 项目类别:
Standard Grant
Graduating in Austerity: Do Welfare Cuts Affect the Career Path of University Students?
紧缩毕业:福利削减会影响大学生的职业道路吗?
- 批准号:
ES/Z502595/1 - 财政年份:2024
- 资助金额:
$ 35.71万 - 项目类别:
Fellowship
Insecure lives and the policy disconnect: How multiple insecurities affect Levelling Up and what joined-up policy can do to help
不安全的生活和政策脱节:多种不安全因素如何影响升级以及联合政策可以提供哪些帮助
- 批准号:
ES/Z000149/1 - 财政年份:2024
- 资助金额:
$ 35.71万 - 项目类别:
Research Grant
感性個人差指標 Affect-X の構築とビスポークAIサービスの基盤確立
建立个人敏感度指数 Affect-X 并为定制人工智能服务奠定基础
- 批准号:
23K24936 - 财政年份:2024
- 资助金额:
$ 35.71万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
How does metal binding affect the function of proteins targeted by a devastating pathogen of cereal crops?
金属结合如何影响谷类作物毁灭性病原体靶向的蛋白质的功能?
- 批准号:
2901648 - 财政年份:2024
- 资助金额:
$ 35.71万 - 项目类别:
Studentship
Investigating how double-negative T cells affect anti-leukemic and GvHD-inducing activities of conventional T cells
研究双阴性 T 细胞如何影响传统 T 细胞的抗白血病和 GvHD 诱导活性
- 批准号:
488039 - 财政年份:2023
- 资助金额:
$ 35.71万 - 项目类别:
Operating Grants
New Tendencies of French Film Theory: Representation, Body, Affect
法国电影理论新动向:再现、身体、情感
- 批准号:
23K00129 - 财政年份:2023
- 资助金额:
$ 35.71万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
The Protruding Void: Mystical Affect in Samuel Beckett's Prose
突出的虚空:塞缪尔·贝克特散文中的神秘影响
- 批准号:
2883985 - 财政年份:2023
- 资助金额:
$ 35.71万 - 项目类别:
Studentship