Targeting protein-protein interactions of Bmi1 oncoprotein
靶向 Bmi1 癌蛋白的蛋白质-蛋白质相互作用
基本信息
- 批准号:9533499
- 负责人:
- 金额:$ 31.97万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-08-01 至 2020-07-31
- 项目状态:已结题
- 来源:
- 关键词:AffinityAmino AcidsAnimal ModelAntineoplastic AgentsB-LymphocytesBindingBiochemicalBiological AssayBiologyBiophysicsCDKN2A geneCancer PatientCancer PrognosisCell Cycle RegulationCellsCellular AssayChemicalsChimeric ProteinsCo-ImmunoprecipitationsCollaborationsComplexDevelopmentDoseDrug TargetingEvaluationFluorescence PolarizationFoundationsFutureGenesGenomicsGoalsIn VitroLeadLeukemic CellLibrariesMalignant NeoplasmsMeasuresMediatingMeninMethodsMichiganMoloney Leukemia VirusN-terminalOncogenesOncogenicOncoproteinsPerformancePlayPolycombPolyhomeoticPropertyProtein Binding DomainProteinsRARA geneRecurrenceReportingResearchResearch PersonnelRoleSiteStem Cell ResearchStem cellsStructureStructure-Activity RelationshipT-Cell LeukemiaTestingTranscription Repressor/CorepressorTumor Suppressor ProteinsUbiquitinationUniversitiesX-Ray CrystallographyZNF145 geneZinc Fingersanalogbasecancer cellcancer stem celldrug discoveryexperienceexperimental studyhigh throughput screeningin vivoin vivo Modelinhibitor/antagonistinnovationinterdisciplinary approachlead optimizationleukemialeukemic stem cellnew therapeutic targetnovelnovel anticancer drugnovel strategiesnovel therapeuticsoverexpressionprotein protein interactionscreeningself-renewalsmall moleculesmall molecule inhibitorsmall molecule librariesstem cell biologystructural biologytargeted cancer therapytranscription factortumor growthtumor progressionubiquitin-protein ligase
项目摘要
Project Summary
Bmi1 (B-cell specific Moloney murine virus insertion site 1) gene has been identified as an oncogene in
multiple cancers, inducing B- and T-cell leukemias. Bmi1 is a stem cell gene, which determines the proliferative
capacity and self-renewal of normal and leukemic stem cells. Multiple studies identified Bmi1 protein to induce
oncogenic transformation and promote tumor growth in a variety of in vitro and in vivo models. Therefore,
targeting Bmi1 activity represents a very promising approach for development of novel therapeutics and
attractive agents to eradicate cancer stem cells.
Bmi1 protein is a component of the polycomb suppressive complex 1 (PRC1), and has been shown to
play a critical role in cell cycle regulation by acting as a transcriptional repressor of INK4a/ARF locus encoding
two important tumor suppressors p16Ink4a and p14Arf. Bmi1 is a relatively small, 37 kDa protein composed of
N-terminal RING domain which has E3 ubiquitin ligase activity and the second domain (B2D, the Bmi1 2nd
domain) which represents a protein-protein interaction motif. Protein-protein interactions of the B2D domain
are essential for Bmi1 activity. It has been shown that B2D is involved in the interactions with polyhomeotic
proteins within the PRC1 complex as well as with the zinc-finger transcription factors E4F1, Zfp277 and PLZF-
RARA fusion protein.
In this project we propose to develop small molecule inhibitors targeting the B2D protein-protein
interaction domain of Bmi1 as new chemical probes to further study the role of B2D domain of Bmi1 and to
identify new potential anti-cancer agents. We have already characterized the interaction of B2D domain of
Bmi1 with PHC2 and developed high quality biochemical assays suitable for screening of small molecule
libraries. We will carry out high-throughput screening at the Center for Chemical Genomics (CCG) at the
University of Michigan to identify small molecule inhibitors of this protein-protein interaction. We will employ
interdisciplinary approach combining biochemical assays, biophysical experiments and structural biology
methods to validate HTS hits and identify high quality small molecule inhibitors of Bmi1. Activity of the most
potent inhibitors will be evaluated in a panel of cell-based experiments to assess their capability to inhibit the
self-renewal properties of leukemic cells. Our project represents a very novel and innovative approach to target
Bmi1 through blocking the protein-protein interactions as currently there are no inhibitors of Bmi1. In summary,
we expect to identify highly valuable compounds that can serve as chemical probes suitable for mechanistic
studies and for further development into potent in vivo inhibitors of the oncogenic Bmi1.
项目概要
Bmi1(B 细胞特异性莫洛尼鼠病毒插入位点 1)基因已被鉴定为癌基因
多种癌症,诱发 B 细胞和 T 细胞白血病。 Bmi1是干细胞基因,决定增殖能力
正常和白血病干细胞的能力和自我更新。多项研究发现 Bmi1 蛋白可诱导
在各种体外和体内模型中致癌转化并促进肿瘤生长。所以,
靶向 Bmi1 活性代表了一种非常有前途的新疗法开发方法
消灭癌症干细胞的有吸引力的药物。
Bmi1 蛋白是多梳抑制复合物 1 (PRC1) 的组成部分,并已被证明可以
作为 INK4a/ARF 位点编码的转录抑制因子,在细胞周期调节中发挥关键作用
两个重要的肿瘤抑制因子 p16Ink4a 和 p14Arf。 Bmi1 是一种相对较小的 37 kDa 蛋白质,由
N 端 RING 结构域具有 E3 泛素连接酶活性和第二个结构域(B2D,Bmi1 第二个结构域)
域),代表蛋白质-蛋白质相互作用基序。 B2D 结构域的蛋白质-蛋白质相互作用
对于 Bmi1 活性至关重要。已表明 B2D 参与与多同源异型的相互作用
PRC1 复合体中的蛋白质以及锌指转录因子 E4F1、Zfp277 和 PLZF-
RARA融合蛋白。
在这个项目中,我们建议开发针对 B2D 蛋白-蛋白的小分子抑制剂
Bmi1的相互作用结构域作为新的化学探针,以进一步研究Bmi1的B2D结构域的作用并
识别新的潜在抗癌药物。我们已经描述了 B2D 域的交互
Bmi1 与 PHC2 并开发了适合筛选小分子的高质量生化检测
图书馆。我们将在化学基因组学中心(CCG)进行高通量筛选。
密歇根大学确定了这种蛋白质-蛋白质相互作用的小分子抑制剂。我们将聘用
结合生化分析、生物物理实验和结构生物学的跨学科方法
验证 HTS 命中并鉴定高质量 Bmi1 小分子抑制剂的方法。活动最多的
有效的抑制剂将在一组基于细胞的实验中进行评估,以评估它们抑制
白血病细胞的自我更新特性。我们的项目代表了一种非常新颖和创新的目标方法
Bmi1 通过阻断蛋白质-蛋白质相互作用来实现,目前尚无 Bmi1 抑制剂。总之,
我们期望识别出非常有价值的化合物,可以作为适合机械学的化学探针
研究并进一步开发成致癌 Bmi1 的有效体内抑制剂。
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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{{ truncateString('Jolanta Grembecka', 18)}}的其他基金
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Development of novel anti-leukemia agents targeting the menin-MLL interaction
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