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
基本信息
- 批准号:10616478
- 负责人:
- 金额:$ 50.31万
- 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:2021-04-01 至 2026-03-31
- 项目状态:未结题
- 来源:
- 关键词:AcetylationAcute Lymphocytic LeukemiaAcute Myelocytic LeukemiaApoptosisBiochemicalBiological AssayBiophysicsCell Membrane PermeabilityCell ProliferationCell modelCellsChemicalsChildhood LeukemiaChromatinChromosomal translocationClinicComplexDevelopmentDiseaseDrug KineticsDrug TargetingENL ProteinEvolutionExcretory functionFutureGene ExpressionGene RearrangementGrowthHistone AcetylationHistone H3HistonesHumanIn VitroInfantKnock-outLeadLeukemic CellLigandsLinkLysineMLL geneMLLT3 geneMetabolismMethylationMethyltransferaseMixed-Lineage LeukemiaMolecularNatureOncogenicPathogenesisPathway interactionsPatientsPharmacologyPhenocopyPrognosisProliferatingPropertyProtacPublic HealthReaderReportingResearchTechnologyTestingTherapeuticToxic effectTranslatingabsorptioncell killingdesigndriver mutationdrug candidateeffective therapyefficacy evaluationgene translocationhistone methyltransferasein vivoinhibitorinnovationleukemiamouse modelnovelnovel therapeutic interventionpharmacologicprotein degradationprototyperesponsesmall moleculesmall molecule inhibitorstandard caretherapeutic targettherapeutically effectivetranscriptomeubiquitin-protein ligase
项目摘要
PROJECT SUMMARY
The mixed-lineage leukemia (MLL) gene rearrangements account for approximately 80% of infant acute
lymphoblastic leukemia (ALL) and 35-50% of infant acute myeloid leukemia (AML). Patients bearing
rearrangements of the MLL gene are associated with dismal prognosis. To date, no effective therapies have
been approved for treating the fatal diseases. Molecularly, inter-chromosomal translocations of MLL lead to in
frame fusions of the N-terminus of MLL to the C-terminus of various fusion partners, which are known as the
“driver” lesions of the diseases. Among more than 70 MLL fusion partners, a small subset of fusions account for
most leukemogenic cases. In ALL, over 90% MLL rearrangements involve only four fusion partners: AFF1, AF9,
ENL, and AF10, all of which are components of the super elongation complex (SEC) or the complex of the
histone H3K79 methyltransferase DOT1L. It is believed that these MLL fusions share a common pathway by
hijacking the SEC or DOT1L complex to promote aberrant activation of the target genes of MLL fusions, leading
to the pathogenesis of leukemias. We and others have recently demonstrated that ENL, a component of the
SEC and DOT1L complex, is critical for the oncogenic function of the MLL-fusions. ENL contains an evolutionally
conserved YEATS domain that we identified as a reader of histone acetylation. We also found that the YEATS
domain of ENL, but not AF9, is essential for growth and survival of the MLL-rearranged leukemic cells. These
key findings strongly suggest that ENL is a promising therapeutic target for MLL-rearranged leukemias. However,
while a recently reported small-molecule inhibitor effectively blocks the interactions between the YEATS domain
of ENL/AF9 and acetylated histone H3, this ENL inhibitor has little or no effect on killing ENL-dependent MLL-
rearranged leukemia cells, failing to phenocopy the cell killing effect of ENL knockout. We hypothesize that
pharmacological degradation of ENL, instead of ENL inhibition that relies on occupancy-driven pharmacology,
will provide a novel and effective therapeutic strategy for treating MLL-rearranged leukemias. To test this
hypothesis, we propose to develop first-in-class ENL small-molecule degraders as in vivo chemical probes using
the proteolysis targeting chimera (PROTAC) technology and evaluate them in MLL-rearranged leukemia cells
and mouse models. We have generated promising preliminary results, suggesting that the proposed research is
feasible. The ENL degrader in vivo chemical probes generated in this project will not only help us test and validate
our therapeutic hypothesis, but can also be further optimized into drug candidates in the future and ultimately
translated in the clinic for MLL-rearranged leukemia patients.
项目摘要
混合系白血病(MLL)基因重排约占婴儿急性白血病的80%。
淋巴母细胞白血病(ALL)和35-50%的婴儿急性髓细胞白血病(AML)。患者轴承
MLL基因重排与预后不良有关。到目前为止,没有有效的治疗方法
被批准用于治疗致命疾病。在分子水平上,MLL的染色体间易位导致了
MLL的N-末端与各种融合配偶体的C-末端的框融合,其被称为
“司机”病变的疾病。在超过70个MLL融合伴侣中,一小部分融合占了
大多数白血病病例在ALL中,超过90%的MLL重排仅涉及四种融合伴侣:AFF 1,AF 9,
ENL和AF 10,所有这些都是超延伸复合物(SEC)的组分,或
组蛋白H3 K79甲基转移酶DOT 1 L。据信,这些MLL融合体通过以下途径共享共同的途径:
劫持SEC或DOT 1 L复合物以促进MLL融合物的靶基因的异常激活,
白血病的发病机制我们和其他人最近证明,ENL是
SEC和DOT 1 L复合物对于MLL融合体的致癌功能至关重要。ENL包含一个进化的
保守的YEATS结构域,我们确定为组蛋白乙酰化的读者。我们还发现叶慈夫妇
ENL的结构域,而不是AF 9,是MLL重排的白血病细胞的生长和存活所必需的。这些
关键的发现有力地表明ENL是MLL重排白血病的有希望的治疗靶点。然而,在这方面,
而最近报道的小分子抑制剂有效地阻断了YEATS结构域之间的相互作用,
ENL/AF 9和乙酰化组蛋白H3的抑制剂,这种ENL抑制剂对杀死ENL依赖性MLL的作用很小或没有作用。
重排的白血病细胞,未能表型复制ENL敲除的细胞杀伤作用。我们假设
ENL的药理学降解,而不是依赖于占用驱动的药理学的ENL抑制,
将为治疗MLL重排白血病提供一种新的有效的治疗策略。为了验证这一
假设,我们建议开发一流的ENL小分子降解剂作为体内化学探针,
蛋白水解靶向嵌合体(PROTAC)技术,并在MLL重排白血病细胞中进行评价
和小鼠模型。我们已经产生了有希望的初步结果,表明拟议的研究是
可行本项目中生成的ENL降解剂体内化学探针不仅有助于我们测试和验证
我们的治疗假设,但也可以在未来进一步优化为候选药物,
在临床上用于MLL重排的白血病患者。
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的其他文献
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Discovery of First-in-class WDR5 PROTACs as a Novel Therapeutic Strategy for MLL-rearranged Leukemias
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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
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$ 50.31万 - 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
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10372195 - 财政年份:2021
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