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.
项目总结/摘要
该提案的长期目标是探索蛋白质二聚化界面作为治疗性疾病的领域。
干预蛋白质二聚化/寡聚化是生物学中反复出现的主题,代表了蛋白质二聚化/寡聚化的机制。
数百种蛋白质通过其调节关键的细胞过程,如酶活性和信号转导。
这种非共价蛋白质同源或异源二聚化是由疏水性以及形状和电荷介导的
互补性二聚体接口曾经被认为是不可用的,现在正成为一个强大的
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
该提案的一个重要目的是开发一种临床相关的小蛋白二聚化抑制剂。作为模型,我们将使用
我们的Bcr-Abl的二聚化卷曲螺旋(cc)抑制剂Bcr-Abl是必须二聚化以
使其具有致癌活性。Bcr-Abl是由异常染色体易位引起的,表现为一种
组成性活性酪氨酸激酶和95%的慢性髓性白血病(CML)的原因。我们建立在
一种新的计算设计的Bcr卷曲螺旋突变体(ccmut),它选择性地与Bcr-Abl二聚化,并抑制
其活动。当作为基因病毒递送时,ccmut对野生型和突变型Bcr-Abl有效。
我们的ccmut特别有利于与Bcr-Abl异源二聚化,以破坏Bcr-Abl二聚化,这是Bcr-Abl二聚化的必要步骤。
肿瘤发生,因此代表了一种新的治疗策略。我们还把ccmut和无毒细胞融合在一起-
具有已知白血病细胞特异性的穿透肽,并显示其破坏Bcr-Abl二聚化,
进入并杀死白血病细胞对于这项提案,我们将探索肽钉合技术(以增加
蛋白水解稳定性)和天然化学连接以将2个较短的钉合肽合成为较长的治疗肽
蛋白质结构域我们将首先计算模型可能的吻合位置,保持目标的亲和力。这些
预期钉合形式(CPP-St-ccmut)进入细胞,抵抗血清蛋白水解,结合Bcr-Abl并抑制Bcr-Abl的表达。
其活动。然后,我们将测试我们的构建体在有和没有TKI泊那替尼的情况下的活性,以测试“多结构域
在CML细胞系、CML患者样品和CML动物模型中Bcr-Abl的“靶向”。目标如下:
1:计算设计和合成与固态肽合成和天然化学连接,a
针对Bc-Abl白血病特异性钉合α抑制剂(CPP-St-ccmut)目的2:测定细胞内化,
CPP-St-ccmut候选物在白血病细胞系中的结合和凋亡能力,
对TKI耐药的相关突变,以及源自患者样本的细胞,单独或联合使用
关于Ponatinib目的3:在简单的临床前试验中证明CPP-St-ccmut在联合和不联合泊那替尼的情况下的疗效
CML的小鼠模型(使用静脉内注射的表达药物的BaF/3细胞的同基因小鼠模型,
抗性Bcr-Abl变体,包括复合突变体)。我们的目标是开发一种钉合蛋白结构域
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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