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
基本信息
- 批准号:10908135
- 负责人:
- 金额:$ 23.07万
- 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:2022-01-01 至 2026-12-31
- 项目状态:未结题
- 来源:
- 关键词:AccountingAcute Lymphocytic LeukemiaAcute leukemiaAffectBindingBiological AvailabilityCCNE1 geneCancer ModelCancer PatientCatalytic DomainCell modelChemicalsChromatinClinicalComplexDevelopmentDiseaseDissectionDoseDrug KineticsDrug TargetingEP300 geneEZH2 geneEnhancersExhibitsGene ActivationGenesGenetically Engineered MouseGenomicsGoalsHistone H3HistonesHomologous GeneHumanIn VitroInfantKnock-outLeadLeftLeukemic CellLigandsLinkLysineMLL geneMediatingModelingMusOncogene ActivationOncogenesOncogenicOncoproteinsOralOutcomePathway interactionsPatientsPhenotypePolycombPrognosisPropertyProtacPublic HealthPublishingReportingRepressionResearchRoleSeriesSiteSolidTechnologyTestingTherapeuticTherapeutic EffectTransactivationXenograft procedureantitumor effectc-myc Genescancer cellcofactordesigndrug candidateeffective therapygene repressionhistone methylationhistone methyltransferaseimprovedin vivoinhibitorinnovationinsightknock-downlead seriesleukemianeoplastic cellnovelnovel therapeutic interventionnovel therapeuticspatient derived xenograft modelpediatric acute leukemiarecruitresponsesmall moleculestandard caretargeted treatmenttherapeutic candidatetumortumorigenesistumorigenicubiquitin-protein ligase
项目摘要
PROJECT SUMMARY/ABSTRACT
Leukemia patients bearing MLL1 rearrangement generally display very poor prognosis, demanding new
treatment strategies. Multiple independent studies have identified EZH2, a histone methyltransferase and
catalytic subunit of Polycomb Repressive Complex 2 (PRC2), as an attractive drug target in MLL1-rearranged
leukemias. However, the current catalytic inhibitors of EZH2 have limited anti-tumor effect. Our preliminary
studies show that EZH2 also binds c-MYC and has a non-canonical function in activation of oncogenes (such
as Cyclin E1) in MLL1-rearranged leukemias, which differs from the well-known PRC2:EZH2-driven canonical
function related to gene repression. In order to target both canonical and non-canonical oncogenic actions by
EZH2, we used the Proteolysis Targeting Chimera (PROTAC) technology to generate novel EZH2 small-
molecule degraders including MS177. Our extensive preliminary studies have demonstrated that MS177
effectively degrades both PRC2:EZH2 and non-PRC2 partners of EZH2 (e.g., c-MYC, which binds EZH2 to
activate oncogenes), thus suppressing both canonical and non-canonical oncogenic activities of EZH2 in
tumor. Importantly, our preliminary results also show that MS177 is superior to all of enzymatic inhibitors of
EZH2 in treating MLL1-rearranged leukemias. Thus, we hypothesize that: (1) EZH2 has a less-studied, non-
canonical oncogenic function, which acts in parallel with the PRC2:EZH2-dependent one to produce more
aggressive tumor phenotypes seen in MLL1-rearranged leukemias; and (2) targeting both canonical and non-
canonical activities of EZH2 by PROTACs represents a novel and superior therapeutic strategy to inhibition of
EZH2’s enzymatic activity alone. Dissection of the mechanisms underlying EZH2-mediated oncogenesis and
development of an optimal EZH2 PROTAC as a drug candidate will have significant impact on improving
treatments for MLL1-rearranged leukemia patients. Towards this goal, we will further characterize such a new
non-canonical oncogenic role of EZH2 in MLL1-rearranged leukemias (Aim 1a) and define effects of EZH2
PROTACs on suppressing both canonical and non-canonical oncogenic activities of EZH2 (Aim 1b). We will
also determine in vitro and vivo therapeutic effects of EZH2 PROTACs by employing multiple independent
MLL1-rearranged leukemia models including human/murine cancer cells and patient-derived xenografts (PDX)
(Aim 2). Lastly, we will optimize our EZH2 PROTAC leads into a drug candidate (Aim 3). Completion of the
proposed research will not only provide novel mechanistic understanding of how MLL1-rearranged leukemias
develop, but will also validate an innovative therapeutic strategy and deliver a promising therapeutic candidate
for the treatment of affected cancer patients.
项目摘要/摘要
携带MLL1重排的白血病患者通常表现出非常差的预后,需要新的
治疗策略。多项独立研究已确定EZH2,一种组蛋白甲基转移酶和
多梳抑制复合体2的催化亚基作为MLL1重排的诱人药物靶点
白血病。然而,目前EZH2的催化抑制剂抗肿瘤作用有限。我们的预赛
研究表明,EZH2还与c-myc结合,并在癌基因(如
在MLL1重排的白血病中,它不同于众所周知的PRC2:EZH2驱动的规范
与基因抑制相关的功能。为了同时针对规范和非规范致癌作用,通过
EZH2,我们利用蛋白质水解靶向嵌合体(PROTAC)技术产生了新型的EZH2小分子-
分子降解剂包括MS177。我们广泛的初步研究表明,MS177
有效地降低PRC2:EZH2和EZH2的非PRC2合作伙伴(例如,将EZH2绑定到
激活癌基因),从而抑制EZH2的典型和非典型致癌活性
肿瘤。重要的是,我们的初步结果还表明,MS177优于所有的酶抑制剂
EZH2治疗MLL1重排白血病因此,我们假设:(1)EZH2具有一个较少研究的、非
规范致癌功能,与PRC2并行作用:依赖于EZH2的功能产生更多
MLL1重排白血病中的侵袭性肿瘤表型;以及(2)针对典型和非典型性白血病
PROTACs对EZH2的规范活性代表了一种新的、优越的治疗策略
鄂州医科大学硕士学位论文S单独酶活。EZH2介导的肿瘤发生和发展机制的剖析
作为候选药物的最佳EZH2 PROTAC的开发将对改进
MLL1重排白血病患者的治疗。为了实现这一目标,我们将进一步表征这样一个新的
EZH2在MLL1重排白血病中的非典型致癌作用(目标1a)及确定EZH2的作用
抑制EZH2的典型和非典型致癌活性的PROTAC(目标1b)。我们会
用多个独立的方法测定EZH2 PROTACs的体内外治疗效果
包括人/鼠癌细胞和患者来源的异种移植(PDX)的MLL1重排白血病模型
(目标2)。最后,我们将优化我们的EZH2 PROTAC线索,使其成为候选药物(目标3)。已完成的
拟议中的研究不仅将为MLL1重排白血病如何发生提供新的机制理解
开发,但也将验证创新的治疗策略并提供有前景的候选治疗方案
用于治疗受影响的癌症患者。
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:
$ 23.07万 - 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:
$ 23.07万 - 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:
$ 23.07万 - 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:
$ 23.07万 - 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:
10387368 - 财政年份:2022
- 资助金额:
$ 23.07万 - 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:
$ 23.07万 - 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:
$ 23.07万 - 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:
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- 资助金额:
$ 23.07万 - 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
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$ 23.07万 - 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:
$ 23.07万 - 项目类别:
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