A Leukemia Cell-Specific Coiled-Coil Protein for Treatment of Chronic Myeloid Leukemia
用于治疗慢性粒细胞白血病的白血病细胞特异性卷曲螺旋蛋白
基本信息
- 批准号:10319608
- 负责人:
- 金额:$ 34.19万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-01-01 至 2025-12-31
- 项目状态:未结题
- 来源:
- 关键词:Acute Lymphocytic LeukemiaAffinityAmino AcidsApoptosisApoptoticAreaBcr-Abl tyrosine kinaseBindingBiologyBlood CirculationBypassCell LineCell physiologyCellsChargeChemicalsChromosomal translocationChromosome abnormalityChronic Myeloid LeukemiaClinicalClinical TrialsCollaborationsCombination Drug TherapyCombined Modality TherapyComputer ModelsDimerizationDiseaseDrug resistanceEventExperimental LeukemiaGenesGenetic DiseasesGoalsGrowthHeterodimerizationHomoHomodimerizationHydrophobicityIndividualInflammatoryIntravenousLeadLengthLeukemic CellLigationLocationMalignant NeoplasmsMediatingModelingOncogenicPainPatientsPeptide SynthesisPeptidesPermeabilityPhasePhosphotransferasesPhysiological ProcessesProductionProtein Tyrosine KinaseProteinsProteolysisResearch PersonnelResistanceSamplingSerumShapesSignal TransductionSolidSpecificityTechnologyTertiary Protein StructureTestingTherapeuticTherapeutic InterventionTranslationsTyrosine Kinase InhibitorVariantViralcell killingchronic myeloid leukemia cellclinically relevantdesigndimerdrug discoveryimprovedin vitro testingin vivoinhibitorleukemiamouse modelmutantmutational statusnew technologynovelnovel therapeutic interventionpre-clinicalprotein oligomerresistance mutationsolid statestandard of carestapled peptidesuccesstargeted agenttargeted treatmenttherapeutic proteintumorigenesis
项目摘要
Project Summary/Abstract
The long-term goals of this proposal are to explore the protein dimerization interface as an area for therapeutic
intervention. Protein dimerization/oligomerization is a recurring theme in biology representing the mechanism
by which hundreds of proteins regulate key cellular processes such as enzymatic activity and signal transduction.
This non-covalent protein homo- or heterodimerization is mediated by hydrophobicity and both shape and charge
complementarity. Once thought to be undruggable, dimer interfaces are emerging as an area for powerful
therapeutic intervention for inflammatory diseases, pain, genetic diseases, cancer, and other diseases. The goal
of this proposal is to develop a clinically relevant small protein dimerization inhibitor. As a model, we will use
our dimerization coiled-coil (cc) inhibitor of Bcr-Abl. Bcr-Abl is an example of a protein that must dimerize to
enable its oncogenic activity. Bcr-Abl, results from an abnormal chromosomal translocation, manifests as a
constitutively active tyrosine kinase and causes of 95% of chronic myeloid leukemias (CML). We build on our
novel, computationally designed Bcr coiled-coil mutant (ccmut) that selectively dimerizes with Bcr-Abl and inhibits
its activity. When virally delivered as a gene, ccmut is effective against wild-type and mutant forms of Bcr-Abl.
Our ccmut specifically favors heterodimerization with Bcr-Abl to disrupt Bcr-Abl dimerization, a necessary step for
oncogenesis, and thus represents a novel therapeutic strategy. We have also fused ccmut to a non-toxic cell-
penetrating peptide with known leukemia cell specificity and showed that it disrupts Bcr-Abl dimerization and
enters and kills leukemia cells. For this proposal, we will explore peptide stapling technologies (to increase
proteolytic stability) and native chemical ligation to synthesize 2 shorter stapled peptides into a longer therapeutic
protein domain. We will first computationally model possible staple locations that maintain target affinity. These
stapled versions (CPP-St-ccmut) are predicted to enter cells, resist serum proteolysis, bind to Bcr-Abl and inhibit
its activity. We will then test the activity of our constructs with and without TKI ponatinib to test “multidomain
targeting” of Bcr-Abl in CML cell lines, CML patient samples, and a CML animal model. Aims are as follows: Aim
1: Computationally design and synthesize with solid state peptide synthesis and native chemical ligation, a
leukemia-specific, stapled cc inhibitor (CPP-St-ccmut) against Bc-Abl. Aim 2: Determine cell internalization,
binding, and apoptotic ability of CPP-St-ccmut candidates in leukemic cell lines including those with clinically
relevant mutations that are resistant to TKIs, and cells derived from patient samples, alone and in combination
with ponatinib. Aim 3: Demonstrate efficacy of CPP-St-ccmut with and without ponatinib in a simple, pre-clinical
mouse model of CML (syngeneic mouse model using intravenously injected BaF/3 cells expressing drug-
resistant Bcr-Abl variants, including compound mutants). Our goal is to develop a stapled protein domain
targeting the protein-protein dimerization interface Bcr-Abl kinase.
项目摘要/摘要
这项提议的长期目标是探索蛋白质二聚化界面作为治疗领域
干预。蛋白质二聚/寡聚是生物学中反复出现的一个主题,代表了这种机制
成百上千的蛋白质通过它来调节关键的细胞过程,如酶活性和信号转导。
这种非共价蛋白质的均二聚或异二聚化是由疏水性以及形状和电荷共同介导的。
互补性。曾经被认为是无法下药的,暗淡的界面正在成为一个强大的
对炎症性疾病、疼痛、遗传性疾病、癌症和其他疾病的治疗干预。目标是
这项建议的目的是开发一种具有临床意义的小蛋白二聚化抑制剂。作为一个模型,我们将使用
我们的二聚卷曲(Cc)抑制剂bcr-abl。Bcr-Abl是一种必须二聚为
使其具有致癌活性。Bcr-Abl是由染色体异常易位引起的,表现为
构成活性酪氨酸激酶和95%的慢性髓系白血病(CML)的病因。我们建立在我们的
新型的计算设计的bcr螺旋线圈突变体(Ccmut),它选择性地与bcr-abl二聚并抑制
它的活动。当ccmut作为一个基因以病毒形式传递时,它对野生型和突变型bcr-abl有效。
我们的ccmut特别支持bcr-abl的异二聚化,以破坏bcr-abl的二聚化,这是
因此,它代表了一种新的治疗策略。我们还将ccmut融合到一种无毒细胞-
具有已知白血病细胞特异性的穿透肽,并表明它破坏BCR-Abl二聚化和
进入并杀死白血病细胞。对于这项提议,我们将探索多肽装订技术(以增加
蛋白质降解稳定性)和天然化学连接,以合成2个较短的短链多肽成为较长的治疗性多肽
蛋白质结构域。我们将首先对维持目标亲和力的可能的订钉位置进行计算建模。这些
装订形式(cpp-St-ccmut)被预测进入细胞,抵抗血清蛋白分解,与bcr-Abl结合并抑制
它的活动。然后,我们将测试使用和不使用TKI poatinib的构建的活性,以测试“多域”
在CML细胞系、CML患者样本和CML动物模型中靶向bcr-Abl。目标如下:目标
1:通过计算机设计和合成,采用固相合成和天然化学连接,a
针对BC-Abl的白血病特异性、装订的CC抑制剂(CPP-ST-CCmut)。目标2:确定细胞内化,
CpP-ST-ccmut候选基因在包括临床白血病细胞株在内的白血病细胞系中的结合和凋亡能力
对TKI具有耐药性的相关突变,以及来自患者样本的细胞,单独和组合
使用波纳替尼。目的3:在一项简单的临床前研究中,证明CPP-ST-CCMUT在使用和不使用波那替尼的情况下的疗效
CML小鼠模型(静脉注射表达药物的Baf/3细胞建立同基因小鼠模型)
抗药性bcr-abl变异体,包括复合突变体)。我们的目标是开发一个装订的蛋白质结构域
靶向蛋白质-蛋白质二聚化界面bcr-abl激酶。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Carol S. Lim其他文献
MULTI-DOMAIN TARGETING OF BCR-ABL BY DISRUPTION OF OLIGOMERIZATION AND TYROSINE KINASE INHIBITION: TOWARDS ERADICATION OF CML
通过破坏寡聚化和抑制酪氨酸激酶来靶向 BCR-ABL 的多域:走向根除 CML
- DOI:
- 发表时间:
2014 - 期刊:
- 影响因子:0
- 作者:
Geoffrey D. Miller;David W. Woessner;M. Sirch;Carol S. Lim - 通讯作者:
Carol S. Lim
Model system to study classical nuclear export signals
研究经典核输出信号的模型系统
- DOI:
10.1208/ps040318 - 发表时间:
2008 - 期刊:
- 影响因子:0
- 作者:
C. Kanwal;Henan Li;Carol S. Lim - 通讯作者:
Carol S. Lim
Organelle-specific targeting in drug delivery and design
- DOI:
10.1016/j.addr.2007.06.001 - 发表时间:
2007-08 - 期刊:
- 影响因子:16.1
- 作者:
Carol S. Lim - 通讯作者:
Carol S. Lim
Development of an Effective Therapy for CML
开发 CML 有效疗法
- DOI:
- 发表时间:
2012 - 期刊:
- 影响因子:0
- 作者:
David W. Woessner;Carol S. Lim;M. Deininger - 通讯作者:
M. Deininger
Simultaneous Visualization of the Yellow and Green Forms of the Green Fluorescent Protein in Living Cells
同时观察活细胞中绿色荧光蛋白的黄色和绿色形式
- DOI:
- 发表时间:
1998 - 期刊:
- 影响因子:3.2
- 作者:
C. Baumann;Carol S. Lim;G. Hager - 通讯作者:
G. Hager
Carol S. Lim的其他文献
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{{ truncateString('Carol S. Lim', 18)}}的其他基金
Re-engineered Mitochondrially Targeted p53 Gene Therapy in Liver Cancer
重新设计的线粒体靶向 p53 基因疗法治疗肝癌
- 批准号:
10317129 - 财政年份:2021
- 资助金额:
$ 34.19万 - 项目类别:
A Leukemia Cell-Specific Coiled-Coil Protein for Treatment of Chronic Myeloid Leukemia
用于治疗慢性粒细胞白血病的白血病细胞特异性卷曲螺旋蛋白
- 批准号:
10543539 - 财政年份:2021
- 资助金额:
$ 34.19万 - 项目类别:
Mitochondrially Targeted p53 DBD for Treatment of Ovarian Cancer
线粒体靶向 p53 DBD 治疗卵巢癌
- 批准号:
8957167 - 财政年份:2015
- 资助金额:
$ 34.19万 - 项目类别:
Simultaneous Targeting of p53 to the Nucleus and Mitochondria for Cancer Therapy
p53 同时靶向细胞核和线粒体用于癌症治疗
- 批准号:
8274895 - 财政年份:2010
- 资助金额:
$ 34.19万 - 项目类别:
Simultaneous Targeting of p53 to the Nucleus and Mitochondria for Cancer Therapy
p53 同时靶向细胞核和线粒体用于癌症治疗
- 批准号:
8467689 - 财政年份:2010
- 资助金额:
$ 34.19万 - 项目类别:
Simultaneous Targeting of p53 to the Nucleus and Mitochondria for Cancer Therapy
p53 同时靶向细胞核和线粒体用于癌症治疗
- 批准号:
8100507 - 财政年份:2010
- 资助金额:
$ 34.19万 - 项目类别:
Converting an Oncogene to an Apoptotic Factor by Manipulating Signal Sequences
通过操纵信号序列将癌基因转化为凋亡因子
- 批准号:
7758311 - 财政年份:2008
- 资助金额:
$ 34.19万 - 项目类别:
Converting an Oncogene to an Apoptotic Factor by Manipulating Signal Sequences
通过操纵信号序列将癌基因转化为凋亡因子
- 批准号:
8212586 - 财政年份:2008
- 资助金额:
$ 34.19万 - 项目类别:
Converting an Oncogene to an Apoptotic Factor by Manipulating Signal Sequences
通过操纵信号序列将癌基因转化为凋亡因子
- 批准号:
7388044 - 财政年份:2008
- 资助金额:
$ 34.19万 - 项目类别:
Converting an Oncogene to an Apoptotic Factor by Manipulating Signal Sequences
通过操纵信号序列将癌基因转化为凋亡因子
- 批准号:
7588848 - 财政年份:2008
- 资助金额:
$ 34.19万 - 项目类别:
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