Discovery of First-in-class WDR5 PROTACs as a Novel Therapeutic Strategy for MLL-rearranged Leukemias
发现一流的 WDR5 PROTAC 作为 MLL 重排白血病的新型治疗策略
基本信息
- 批准号:10387368
- 负责人:
- 金额:$ 67.16万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-05-01 至 2027-04-30
- 项目状态:未结题
- 来源:
- 关键词:Acute Lymphocytic LeukemiaAcute Myelocytic LeukemiaAcute leukemiaApoptosisBindingBiological AssayBiophysicsCell Cycle ProgressionCell ProliferationCell modelCellsChemicalsChildhood LeukemiaChromatinClinicClinical TrialsComplexCrystallizationDiseaseDoseDrug KineticsDrug TargetingFutureGene ExpressionGene Expression RegulationGenesGeneticGenetic TranscriptionGrowthHumanIn VitroInfantKnock-outLeadLeukemic CellLigandsLinkMLL geneMalignant NeoplasmsMediatingMixed-Lineage LeukemiaOncogenicOncoproteinsPatientsPharmacologyPrognosisPropertyProtacPublic HealthReportingResearchResolutionStructureTechnologyTertiary Protein StructureTestingTherapeuticToxic effectTranslatingXenograft procedureantitumor effectbasebiophysical propertiesc-myc Genescell killingdesigndrug candidatehistone methyltransferaseimprovedin vivoinhibitorinnovationknock-downleukemiamouse modelnovel therapeutic interventionpatient derived xenograft modelprogramsprotein degradationprotein protein interactionrecruitresponsesmall moleculesmall molecule inhibitorstandard caretargeted treatmenttherapeutic targettooltranscriptometreatment strategytumor growthtumorigenesisubiquitin-protein ligase
项目摘要
PROJECT SUMMARY
Rearrangements of the mixed-lineage leukemia (MLL) gene account for approximately 10% of all human
leukemias. Such rearrangements are more common in pediatric leukemias. Up to 80% of infant acute
lymphoblastic leukemias (ALL) and 35-50% of infant acute myeloid leukemias (AML) are characterized by MLL
rearrangements. MLL-rearranged (MLL-r) leukemia patients have particularly poor response to standard
treatments and a dismal prognosis. To date, no effective targeted therapies have been approved for treating
these deadly cancers. WD40 repeat domain protein 5 (WDR5) is an essential subunit of the MLL1 histone
methyltransferase complex (MLL1 complex) and is crucial for MLL1 complex-mediated regulations of gene
transcription. WDR5 also interacts with non-MLL partners such as c-MYC. Importantly, interactions between
WDR5 and its various binding partners are essential for sustaining oncogenesis, and genetic depletion of WDR5
suppresses the proliferation of MLL-r leukemias. Therefore, WDR5 is a promising drug target for MLL-r
leukemias. However, while small-molecule inhibitors that effectively block the protein-protein interactions (PPI)
between WDR5 and its binding partners have been developed, these WDR5 PPI inhibitors are largely ineffective
in killing MLL-r leukemia cells and lack in vivo efficacy, as opposed to the cell killing effect of WDR5 genetic
knockout or knockdown. We hypothesize that pharmacological degradation of WDR5 by small-molecule
degraders as a novel therapeutic strategy will be effective and superior to pharmacological inhibition of WDR5
by PPI inhibitors for the treatment of MLL-r leukemias. To test this hypothesis, we propose to discover first-in-
class WDR5 small-molecule degraders using the proteolysis targeting chimera (PROTAC) technology and
evaluate them in MLL-r leukemia cellular and mouse models. We have generated very promising preliminary
results, suggesting that the proposed research is feasible. The WDR5 PROTAC degraders generated in this
project will not only help us test our innovative therapeutic hypothesis, but can also be developed further into a
drug candidate for advancing to clinical trials with MLL-r leukemia patients. These WDR5 PROTACs are also
valuable chemical probes for assessing the therapeutic potential of WDR5 degradation in other cancers.
项目总结
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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Jian Jin其他文献
Jian Jin的其他文献
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{{ truncateString('Jian Jin', 18)}}的其他基金
Novel Inhibitors of Lysine Methyltransferases G9a and GLP for the Treatment of Alzheimer's Disease
用于治疗阿尔茨海默病的新型赖氨酸甲基转移酶 G9a 和 GLP 抑制剂
- 批准号:
10752812 - 财政年份:2023
- 资助金额:
$ 67.16万 - 项目类别:
Dissecting and targeting canonical and non-canonical oncogenic functions of EZH2 in cancer
剖析和靶向 EZH2 在癌症中的典型和非典型致癌功能
- 批准号:
10544005 - 财政年份:2022
- 资助金额:
$ 67.16万 - 项目类别:
Dissecting and targeting canonical and non-canonical oncogenic functions of EZH2 in cancer
剖析和靶向 EZH2 在癌症中的典型和非典型致癌功能
- 批准号:
10389877 - 财政年份:2022
- 资助金额:
$ 67.16万 - 项目类别:
Dissecting and targeting canonical and non-canonical oncogenic functions of EZH2 in caner
剖析和靶向 EZH2 在癌症中的典型和非典型致癌功能
- 批准号:
10908135 - 财政年份:2022
- 资助金额:
$ 67.16万 - 项目类别:
Discovery of First-in-class WDR5 PROTACs as a Novel Therapeutic Strategy for MLL-rearranged Leukemias
发现一流的 WDR5 PROTAC 作为 MLL 重排白血病的新型治疗策略
- 批准号:
10712396 - 财政年份:2022
- 资助金额:
$ 67.16万 - 项目类别:
Discovery of First-in-class WDR5 PROTACs as a Novel Therapeutic Strategy for MLL-rearranged Leukemias
发现一流的 WDR5 PROTAC 作为 MLL 重排白血病的新型治疗策略
- 批准号:
10615610 - 财政年份:2022
- 资助金额:
$ 67.16万 - 项目类别:
Discovery of First-in-class WDR5 PROTACs as a Novel Therapeutic Strategy for MLL-rearranged Leukemias
发现一流的 WDR5 PROTAC 作为 MLL 重排白血病的新型治疗策略
- 批准号:
10745902 - 财政年份:2022
- 资助金额:
$ 67.16万 - 项目类别:
Development of Novel PROTACs Targeting the ENL YEATS Domain for Treating MLL-rearranged Leukemias
开发针对 ENL YEATS 结构域的新型 PROTAC,用于治疗 MLL 重排白血病
- 批准号:
10222062 - 财政年份:2021
- 资助金额:
$ 67.16万 - 项目类别:
Development of Novel PROTACs Targeting the ENL YEATS Domain for Treating MLL-rearranged Leukemias
开发针对 ENL YEATS 结构域的新型 PROTAC,用于治疗 MLL 重排白血病
- 批准号:
10372195 - 财政年份:2021
- 资助金额:
$ 67.16万 - 项目类别:
Development of Novel PROTACs Targeting the ENL YEATS Domain for Treating MLL-rearranged Leukemias
开发针对 ENL YEATS 结构域的新型 PROTAC,用于治疗 MLL 重排白血病
- 批准号:
10616478 - 财政年份:2021
- 资助金额:
$ 67.16万 - 项目类别:
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