Mechanisms of Kinase Function and Drug Resistance in Cancer
癌症中激酶功能和耐药性的机制
基本信息
- 批准号:8440329
- 负责人:
- 金额:$ 33.09万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2011
- 资助国家:美国
- 起止时间:2011-07-01 至 2015-03-31
- 项目状态:已结题
- 来源:
- 关键词:Acute Lymphocytic LeukemiaAdverse effectsAffectAllelesArchitectureAutoimmunityAutomobile DrivingB-Cell DevelopmentB-LymphocytesBasic Amino AcidsBindingBinding ProteinsBone MarrowCSNK1A1 geneCancer EtiologyCatalysisCatalytic DomainCellsChimeric ProteinsChronic Myeloid LeukemiaClinicalClinical TrialsComputer ArchitecturesCyclic GMP-Dependent Protein KinasesCytostaticsDataDevelopmentDiseaseDrug TargetingDrug resistanceElectrostaticsExclusionFamilyFollow-Up StudiesFundingGenerationsGleevecHydrogen BondingHyperactive behaviorImatinibIn VitroMalignant NeoplasmsMediatingMetabolismModelingMolecularMusMutagenesisMutationOncogenesPatientsPharmaceutical PreparationsPhosphotransferasesProtein KinaseProteinsPublishingRelapseResistanceRoleSerineSideSodium ChlorideSplenomegalyStructureTest ResultTestingTherapeuticTherapeutic UsesThreonineTimeTriad Acrylic ResinTyrosineVariantbasecasein kinasecell growthcell transformationdesigndrug discoveryimprovedin vitro activityin vivoin vivo Modelinhibitor/antagonistinnovationinsightinterdisciplinary approachkinase inhibitorlyn protein-tyrosine kinasemolecular dynamicsmutantneoplastic cellpatient populationresistance mutationsmall moleculesrc-Family Kinasessuccess
项目摘要
DESCRIPTION (provided by applicant): Kinases are the second-largest drug-target family with 10 approved kinase inhibitor drugs and 50 compounds in clinical trials. Protein-kinase-domains are most frequently encoded by cancer-genes. Several cancer-driving mutations occur in their ATP-binding G-loops. The Abl-inhibitor Imatinib is a breakthrough-therapeutic for chronic-myelogenous-leukemia, but ~35% of the patients relapse due to accumulation of Imatinib-resistant Abl kinase-domain-mutations, particularly in the G-loop. Drug-resistance could thus become a major clincial problem as increasing patient populations are treated with kinase-inhibitor drugs. Using the Src-family protein tyrosine kinase Lyn as an experimentally very tractable example, we propose to implement and validate a multidisciplinary approach that first uses molecular dynamics (MD) simulations to relatively quickly identify mutations that affect catalysis and inhibitor interactions and can cause drug-resistance (Aim 1). Our approach next analyzes the activities, inhibitor-interactions and -resistance of the identified Lyn mutants in vitro and in vivo in Ba/F3 cells (Aim 2) or in Lyn-/- bone-marrow (Aim 3) to identify those mutations that are most relevant physiologically. Exclusion of uninformative mutants at each step minimizes experimental effort and maximizes relevance and likelihood of success. We consider this integrated approach to discover drug-resistance causing kinase mutations highly innovative, because it provides important insight that is usually only gained over much longer time periods and through the efforts of several labs. These studies follow up on our recently published finding that 58 eukaryotic kinases contain a conserved electrostatic salt-bridge across their G-loops that is essential for G-loop-stabilization, catalysis and ATP- or ATP-competitive inhibitor-binding. Salt-bridge- disruption in Bcr-Abl causes Imatinib-resistance. Our preliminary data suggest that in 31 kinases, including the Src, Abl, CK1 and CK2-families which all have important roles in cancer, the acidic salt-bridge-anchor also interacts electrostatically with a conserved polar-aromatic or basic amino-acid-side-chain embedded in a hydrophobic core. To test the hypothesis that this "triad interaction-network" architecture is essential for G-loop function and inhibitor-interactions, and that its disruption can cause drug resistance, we will analyze the effects of mutationally modulating the different components of the variant G-loop-triad-configurations in the exemplary kinases Lyn (Aims 1-3), Abl, CK1(2 and CK2a1 (Aim 4). To keep Aim 4 achievable within the 5 year funding period, we will focus on MD analyses. Future research will analyze the predicted high-priority mutants in vitro and in vivo. We consider this proposal highly significant, because it implements and validates an efficient approach to understand the molecular mechanisms through which a therapeutically very important target class functions, interacts with small-molecule inhibitors and can become drug-resistant. If successful, our approach can be applied to other targets to identify drug-resistant mutants at the onset of a drug discovery project, enabling the structure-based rational design of molecules that inhibit wildtype and mutant kinases potently. This will aid the development of more selective, less side-effect and less drug-resistance prone therapeutics.
描述(由申请人提供):激酶是第二大药物靶点家族,有10种批准的激酶抑制剂药物和50种临床试验化合物。蛋白激酶结构域最常由癌基因编码。几个癌症驱动突变发生在它们的ATP结合G环中。伊马替尼是慢性粒细胞白血病的突破性治疗药物,但约35%的患者因伊马替尼耐药Abl激酶结构域突变的积累而复发,特别是在G环中。因此,随着越来越多的患者使用激酶抑制剂药物治疗,耐药性可能成为一个主要的临床问题。使用Src家族蛋白酪氨酸激酶林恩作为一个实验上非常容易处理的例子,我们建议实施和验证一个多学科的方法,首先使用分子动力学(MD)模拟相对快速地确定突变,影响催化和抑制剂的相互作用,并可能导致耐药性(目标1)。我们的方法接下来在体外和体内在Ba/F3细胞(Aim 2)或林恩-/-骨髓(Aim 3)中分析鉴定的林恩突变体的活性、代谢物相互作用和抗性,以鉴定生理上最相关的那些突变。在每个步骤中排除无信息突变体可以最大限度地减少实验工作,并最大限度地提高相关性和成功的可能性。我们认为这种发现耐药性导致激酶突变的综合方法具有高度创新性,因为它提供了重要的见解,通常只有在更长的时间内并通过几个实验室的努力才能获得。这些研究是我们最近发表的发现的后续,该发现表明58种真核激酶在其G环上含有保守的静电盐桥,该盐桥对于G环稳定、催化和ATP或ATP竞争性底物结合至关重要。Bcr-Abl中的盐桥破坏导致伊马替尼耐药。我们的初步数据表明,在31种激酶中,包括Src、Abl、CK 1和CK 2-家族,它们都在癌症中起重要作用,酸性盐桥锚也与嵌入疏水核心中的保守的极性芳族或碱性氨基酸侧链静电相互作用。为了检验这种“三联体相互作用-网络”结构对于G-环功能和通道相互作用是必需的,并且其破坏可以引起耐药性的假设,我们将分析突变调节示例性激酶林恩(目的1-3)、Abl、CK 1 α 2和CK 2 α 1(目的4)中的变体G-环三联体构型的不同组分的作用。为了确保目标4在5年资助期内实现,我们将专注于MD分析。未来的研究将在体外和体内分析预测的高优先级突变体。我们认为这一提议非常重要,因为它实施并验证了一种有效的方法来理解治疗上非常重要的靶类功能的分子机制,与小分子抑制剂相互作用并可能产生耐药性。如果成功的话,我们的方法可以应用于其他靶点,在药物发现项目开始时识别耐药突变体,从而能够有效抑制野生型和突变型激酶的分子的基于结构的合理设计。这将有助于开发更具选择性、副作用更小、耐药性更低的治疗药物。
项目成果
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Jianwei Che其他文献
Jianwei Che的其他文献
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{{ truncateString('Jianwei Che', 18)}}的其他基金
Mechanisms of Kinase Function and Drug Resistance in Cancer
癌症中激酶功能和耐药性的机制
- 批准号:
8024578 - 财政年份:2011
- 资助金额:
$ 33.09万 - 项目类别:
Mechanisms of Kinase Function and Drug Resistance in Cancer
癌症中激酶功能和耐药性的机制
- 批准号:
8636034 - 财政年份:2011
- 资助金额:
$ 33.09万 - 项目类别:
Mechanisms of Kinase Function and Drug Resistance in Cancer
癌症中激酶功能和耐药性的机制
- 批准号:
8288696 - 财政年份:2011
- 资助金额:
$ 33.09万 - 项目类别:
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