A Novel Screen for Compounds that Outflank BCR-ABL Drug-Resistance
突破 BCR-ABL 耐药性的化合物的新筛选
基本信息
- 批准号:7725809
- 负责人:
- 金额:$ 31.54万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-05-01 至 2012-04-30
- 项目状态:已结题
- 来源:
- 关键词:ABL1 geneActive SitesAddressAdoptedBasic ScienceBindingBiochemistryBiological AssayBiologyBone Marrow CellsCatalytic DomainCategoriesCellsCharacteristicsChronic Myeloid LeukemiaClinicalCollaborationsDiseaseDisease ResistanceDiversity LibraryDrug Delivery SystemsDrug resistanceEnzymesFluorescenceFluorescence Resonance Energy TransferGoalsHumanImatinibIn VitroIncidenceMalignant NeoplasmsModelingMutationOncogene ProteinsOncogenicPatientsPharmaceutical PreparationsPhenotypePhosphotransferasesPhysiologicalProductionPropertyProtein Tyrosine KinaseProteinsReceptor Protein-Tyrosine KinasesRecurrent diseaseRelapseRelative (related person)RepressionResearchResistanceResistance developmentRoleSignal TransductionSiteSystemTechnologyTestingTherapeuticTimeToxic effectTyrosineTyrosine Phosphorylationbasebcr-abl Fusion Proteinscell transformationdesignhigh throughput screeningimprovedin vivoinhibitor/antagonistinnovationkinase inhibitorleukemialeukemogenesismutantnew technologynovelnovel therapeuticspreventprotein protein interactionpublic health relevanceresearch studyresistance mutationresponsesmall molecule librariestherapeutic developmenttherapeutic targettooltyrosine kinase ABL1
项目摘要
DESCRIPTION (provided by applicant): Mutationally activated ABL tyrosine kinases are causative in many leukemias. ABL kinase inhibitors have been useful in treating chronic myeloid leukemia (CML) with a BCR-ABL1 fusion, demonstrating the value of oncoprotein-directed therapeutics. However, some leukemias with activated ABL do not respond to these inhibitors and some CML patients that respond, subsequently become resistant. Resistance, and disease relapse, most often results from BCR-ABL1 kinase domain mutations that maintain kinase activity but prevent inhibitor binding. To understand the mechanism of leukemogenesis, and to explore potential therapeutic targets in kinase inhibitor-resistant leukemias, we examined a physiological activator of ABL kinases. RIN1 directly binds ABL1 and stimulates kinase activity through de-repression of the autoinhibited enzyme. RIN1 strongly stimulates ABL kinases in vitro and in vivo. In addition, RIN1 binds to and enhances the catalytic, transforming and leukemogenic properties of BCR-ABL1. This demonstrates that the tyrosine kinase activity of BCR-ABL1, while elevated and constitutive relative to ABL1, is still responsive to stimulation by RIN1. Deletion of RIN1 blocks transformation of bone marrow cells by BCR-ABL1. Transformation is rescued by re-introduction of RIN1, indicating that this is a cell autonomous phenotype. Silencing of RIN1 in leukemia cells reduced cellular phospho-tyrosine levels and sensitized cells to the ABL inhibitor imatinib. BCR- ABL1T315I, a drug resistant mutant found in CML patients, was also dependent on RIN1 for transformation. The activation of ABL kinases by RIN1 suggests an alternative approach to kinase inhibition: disrupting the interaction with a positive regulator. Because BCR-ABL1 is dependent on RIN1 for full transformation, this represents a unique point of vulnerability that could be exploited to treat kinase inhibitor-resistant leukemias. Combining drugs that inhibit BCR-ABL1 activation by RIN1 with standard ABL kinase inhibitors could provide therapy that is more efficacious and less prone to the development of resistance and disease relapse. We have created an assay that quantifies the collaboration of RIN1 and ABL1. The assay incorporates a novel application of time-resolved fluorescence resonance energy transfer (TR-FRET) and was validated in a high throughput format with robust characteristics (Z' > 0.5). An exceptionally diverse chemical library will be included in a screen for compounds that inhibit the interaction of RIN1 and ABL1. Secondary screens will be used to eliminate false positives and to prioritize inhibitors that can block transformation by BCR-ABL1. This proposal addresses a fundamental question in signal transduction (how are non-receptor tyrosine kinases regulated?), with clear disease relevance (how do leukemogenic ABL kinases transform cells?) and immediate clinical implications (how can resistance to standard kinase inhibitors be prevented or circumvented?). The compounds identified in this screen will be invaluable tools for understanding the biochemistry of normal and oncogenic ABL proteins, and may also serve as leads to new therapeutics. PUBLIC HEALTH RELEVANCE: The proposed research uses a novel assay to identify inhibitors of an ABL tyrosine kinase regulator with a direct role in leukemogenesis. The assay, which includes an innovative use of fluorescence technologies, will be used in a high throughput screen for compounds that block leukemia-associated kinases independently of standard inhibitors. Compounds in this category should be invaluable tools for understanding the biochemistry underlying this disease. Derivatives of such inhibitors may eventually be developed into effective therapeutics against the increasing number of drug resistant leukemias and might synergize with standard kinase inhibitors to reduce the incidence of drug resistance in these and other tyrosine kinase-dependent cancers.
描述(由申请人提供):突变激活的 ABL 酪氨酸激酶是许多白血病的病因。 ABL 激酶抑制剂已可用于通过 BCR-ABL1 融合治疗慢性粒细胞白血病 (CML),证明了癌蛋白导向疗法的价值。然而,一些 ABL 激活的白血病对这些抑制剂没有反应,而一些有反应的 CML 患者随后产生耐药性。耐药性和疾病复发通常是由 BCR-ABL1 激酶结构域突变引起的,这些突变维持激酶活性但阻止抑制剂结合。为了了解白血病发生的机制,并探索激酶抑制剂耐药性白血病的潜在治疗靶点,我们研究了 ABL 激酶的生理激活剂。 RIN1 直接结合 ABL1,并通过解除自身抑制酶的抑制来刺激激酶活性。 RIN1 在体外和体内强烈刺激 ABL 激酶。此外,RIN1 与 BCR-ABL1 结合并增强其催化、转化和致白血病特性。这表明 BCR-ABL1 的酪氨酸激酶活性虽然相对于 ABL1 有所升高且是组成型的,但仍然对 RIN1 的刺激有反应。 RIN1 的缺失会阻止 BCR-ABL1 对骨髓细胞的转化。通过重新引入 RIN1 来挽救转化,表明这是一种细胞自主表型。白血病细胞中 RIN1 的沉默降低了细胞磷酸酪氨酸水平,并使细胞对 ABL 抑制剂伊马替尼敏感。 BCR-ABL1T315I 是一种在 CML 患者中发现的耐药突变体,也依赖于 RIN1 进行转化。 RIN1 对 ABL 激酶的激活表明了另一种激酶抑制方法:破坏与正调节因子的相互作用。由于 BCR-ABL1 依赖于 RIN1 进行完全转化,因此这代表了一个独特的脆弱点,可用于治疗激酶抑制剂耐药性白血病。将抑制 RIN1 激活 BCR-ABL1 的药物与标准 ABL 激酶抑制剂相结合,可以提供更有效且不易产生耐药性和疾病复发的治疗方法。我们创建了一种定量 RIN1 和 ABL1 协作的检测方法。该测定结合了时间分辨荧光共振能量转移 (TR-FRET) 的新颖应用,并以具有稳健特性 (Z' > 0.5) 的高通量格式进行了验证。筛选抑制 RIN1 和 ABL1 相互作用的化合物时将包含异常多样化的化学库。二次筛选将用于消除假阳性并优先考虑可阻止 BCR-ABL1 转化的抑制剂。该提案解决了信号转导中的一个基本问题(非受体酪氨酸激酶如何调节?),具有明确的疾病相关性(致白血病 ABL 激酶如何转化细胞?)和直接的临床意义(如何预防或规避对标准激酶抑制剂的耐药性?)。本次筛选中鉴定出的化合物将成为了解正常和致癌 ABL 蛋白的生物化学的宝贵工具,并且还可以作为新疗法的先导。公共健康相关性:拟议的研究使用一种新的检测方法来鉴定在白血病发生中具有直接作用的 ABL 酪氨酸激酶调节因子的抑制剂。该检测方法包括荧光技术的创新应用,将用于高通量筛选独立于标准抑制剂而阻断白血病相关激酶的化合物。此类化合物应该是了解这种疾病的生物化学的宝贵工具。此类抑制剂的衍生物最终可能被开发成针对日益增加的耐药性白血病的有效疗法,并可能与标准激酶抑制剂协同作用,以降低这些和其他酪氨酸激酶依赖性癌症的耐药性发生率。
项目成果
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JOHN J. COLICELLI其他文献
JOHN J. COLICELLI的其他文献
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{{ truncateString('JOHN J. COLICELLI', 18)}}的其他基金
A Novel Screen for Compounds that Outflank BCR-ABL Drug-Resistance
突破 BCR-ABL 耐药性的化合物的新筛选
- 批准号:
8067981 - 财政年份:2009
- 资助金额:
$ 31.54万 - 项目类别:
Mechanism of RIN1 Signaling in Neuronal Plasticity
RIN1 信号传导在神经元可塑性中的机制
- 批准号:
6773149 - 财政年份:2003
- 资助金额:
$ 31.54万 - 项目类别:
Mechanism of RIN1 Signaling in Neuronal Plasticity
RIN1 信号传导在神经元可塑性中的机制
- 批准号:
7259412 - 财政年份:2003
- 资助金额:
$ 31.54万 - 项目类别:
Mechanism of RIN1 Signaling in Neuronal Plasticity
RIN1 信号传导在神经元可塑性中的机制
- 批准号:
6681142 - 财政年份:2003
- 资助金额:
$ 31.54万 - 项目类别:
Mechanism of RIN1 Signaling in Neuronal Plasticity
RIN1 信号传导在神经元可塑性中的机制
- 批准号:
7067644 - 财政年份:2003
- 资助金额:
$ 31.54万 - 项目类别:
Mechanism of RIN1 Signaling in Neuronal Plasticity
RIN1 信号传导在神经元可塑性中的机制
- 批准号:
6910730 - 财政年份:2003
- 资助金额:
$ 31.54万 - 项目类别:
MECHANISM OF ENZYME INHIBITION BY PHARMACOLOGICAL AGENTS
药理制剂抑制酶的机制
- 批准号:
2714522 - 财政年份:1993
- 资助金额:
$ 31.54万 - 项目类别:
MECHANISM OF ENZYME INHIBITION BY PHARMACOLOGICAL AGENTS
药理制剂抑制酶的机制
- 批准号:
2037678 - 财政年份:1993
- 资助金额:
$ 31.54万 - 项目类别:
MECHANISM OF ENZYME INHIBITION BY PHARMACOLOGICAL AGENTS
药理制剂抑制酶的机制
- 批准号:
3418801 - 财政年份:1993
- 资助金额:
$ 31.54万 - 项目类别:
MECHANISM OF ENZYME INHIBITION BY PHARMACOLOGICAL AGENTS
药理制剂抑制酶的机制
- 批准号:
2269863 - 财政年份:1993
- 资助金额:
$ 31.54万 - 项目类别:
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