Targeting the menin-MLL1 complex for new therapeutics
靶向 menin-MLL1 复合物的新疗法
基本信息
- 批准号:9889047
- 负责人:
- 金额:$ 64.77万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-04-04 至 2023-03-31
- 项目状态:已结题
- 来源:
- 关键词:Acute Myelocytic LeukemiaAcute leukemiaAddressAdultAdvanced DevelopmentAffinityAllelesAmino AcidsAnimalsAwardBindingBioavailableBiological AssayBiological AvailabilityBone Marrow CellsBone Marrow Stem CellCell LineCell modelChimeric ProteinsChromosomal RearrangementClinical TrialsComplexCrystallizationDevelopmentDisadvantagedDoseDrug KineticsGene ExpressionGoalsHRX proteinHomeobox GenesHumanIn VitroLaboratory ResearchLeadLeukemic CellMEIS1 geneMLL geneMLL2 geneMeninMetabolicMolecular Mechanisms of ActionMusOncogenicOralPatientsPharmacodynamicsPlasmaPropertyProteinsReportingResearchScheduleSeriesSolidSpecificityStructureSurvival RateTherapeuticToxic effectTreatment Efficacyanticancer activitybasecell growthcellular targetingclinical developmentcofactordesignfusion geneimprovedin vivoin vivo evaluationinhibitor/antagonistleukemialeukemogenesismolecular targeted therapiesnanomolarnovelnovel therapeuticsoutcome forecastpreclinical developmentpreclinical studyprotein protein interactionsmall moleculesmall molecule inhibitorsuccesstargeted treatmenttherapeutic targettooltreatment strategy
项目摘要
In 5% of adult human acute myeloid leukemia (AML), chromosomal rearrangements of the
mixed lineage leukemia gene (MLL, also called MLL1 to distinguish it from MLL2-4) occur,
which results in expression of MLL fusion proteins. Patients with leukemia carrying a MLL
translocation (hereafter also called MLL leukemia) have very poor prognosis and only 35%
have a 5-year survival with current treatments, highlighting the urgent need to develop new and
more effective therapeutic approaches for MLL leukemia.
The most common MLL rearrangements are balanced MLL translocations, in which only
one MLL allele is truncated and fused with one of over 70 fusion partners. Approximately 1400
amino acids from the MLL N-terminus are retained in all the MLL fusion proteins, and interact
directly with the oncogenic cofactor menin. The menin-MLL protein-protein interaction is
essential for expression of HOX and MEIS1 genes to drive leukemogenesis in MLL leukemia.
Consequently, targeting the menin-MLL protein-protein interaction using small-molecule
inhibitors is considered to be a promising, molecularly targeted therapeutic strategy for the
treatment of MLL leukemia.
Although design of non-peptide small–molecule inhibitors targeting the menin-MLL protein-
protein interaction has been actively pursued in recent years, the best small-molecule inhibitors
currently available are only excellent laboratory research “tool” compounds for preclinical
studies. Development of small-molecule menin inhibitors for the treatment of MLL leukemia is
still in an early stage of research and no compound has progressed into human clinical trials. In
this R01 award, we propose to design and develop highly potent, specific, orally bioavailable,
non-peptide small-molecule inhibitors of the menin-MLL protein-protein interaction for the
treatment of AML carrying MLL fusion.
在5%的成人急性髓性白血病(AML)中,染色体重排
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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SHAOMENG WANG其他文献
SHAOMENG WANG的其他文献
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{{ truncateString('SHAOMENG WANG', 18)}}的其他基金
Targeting the menin-MLL1 complex for new therapeutics
靶向 menin-MLL1 复合物的新疗法
- 批准号:
10379367 - 财政年份:2018
- 资助金额:
$ 64.77万 - 项目类别:
Project 3: Exploring Ablation of the Androgen Receptor as a Therapeutic Approach for Castration-Resistant Prostate Cancer
项目 3:探索雄激素受体消融作为去势抵抗性前列腺癌的治疗方法
- 批准号:
10705234 - 财政年份:2014
- 资助金额:
$ 64.77万 - 项目类别:
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