Targeting histone methyltransferase EZH2 for the treatment of hematological cancer

靶向组蛋白甲基转移酶 EZH2 治疗血液癌

• 批准号: 10580588
• 负责人: A-Rum Kim
• 金额: $ 3.03万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10580588
• 关键词: Acute Myelocytic Leukemia; Acute leukemia; Adult Acute Lymphocytic Leukemia; Adult Acute Myeloblastic Leukemia; Antineoplastic Agents; Binding; Biology; CCNE1 gene; Cancer Biology; Cancer Patient; Catalytic Domain; Cells; Chemicals; Chromatin; Clinic; Clinical; Collaborations; Combined Modality Therapy; Complex; Dependence; Deposition; Dose; Drug Kinetics; Drug Targeting; Enhancers; Ensure; Epigenetic Process; Event; Exhibits; FDA approved; Fellowship; Gene Activation; Gene Expression; Gene Rearrangement; Gene Targeting; Genes; Genetic; Genetically Engineered Mouse; Genomic approach; Genomics; Growth; Hematologic Neoplasms; Histone H3; Histones; Homologous Gene; Human; In Vitro; Knock-out; Lead; Left; Leukemic Cell; Lysine; MLL gene; MLL-rearranged leukemia; Malignant Neoplasms; Modeling; Molecular; Mus; Oncogenes; Oncogenic; Outcome; Patients; Pharmaceutical Preparations; Pharmacotherapy; Polycomb; Positioning Attribute; Prognosis; Proliferating; Protac; Proteins; Publishing; Regimen; Regulator Genes; Reporting; Repression; Research Personnel; Role; Site; Technology; Therapeutic Agents; Therapeutic Effect; Training; Tumorigenicity; Xenograft Model; acute myeloid leukemia cell; anti-cancer; antitumor effect; cancer therapy; cell growth; clinical application; design; gene repression; histone methylation; histone methyltransferase; in vivo; in vivo Model; infancy; inhibitor; innovation; knock-down; leukemia; mouse model; multicatalytic endopeptidase complex; neoplastic cell; novel; novel therapeutic intervention; patient derived xenograft model; pharmacologic; pre-clinical; screening; small molecule; targeted agent; therapeutic target; therapeutically effective; transcriptomics; treatment effect; treatment strategy; tumor; tumor growth; tumorigenesis; ubiquitin-protein ligase

PROJECT SUMMARY & ABSTRACT Enhancer of Zeste Homolog 2 (EZH2), the catalytic subunit of Polycomb Repressive Complex 2 (PRC2), induces trimethylation of histone H3 lysine 27 (H3K27me3) for repressing the target gene expression. Numerous studies have reported that EZH2 promotes oncogenesis in a range of human cancers. In particular, independent studies have demonstrated the expression of EZH2 to be essential for tumorigenicity of acute leukemias with the Mixed Lineage Leukemia gene rearrangement (MLL-r), which accounts for approximately 60–80% of infantile and ~10% of adult acute lymphoblastic leukemia (ALL) cases, as well as ~50% of infantile and ~7% of adult acute myeloid leukemia (AML) cases. Leukemia patients with MLL-r generally exhibit very poor prognosis in the clinic, demanding new treatment strategies. However, increasing evidence including ours now support that EZH2’s oncogenic functions go beyond PRC2 and its enzymatic function for H3K27me3 deposition, and has the new, PRC2-independent activity (non-canonical) to sustain oncogenesis. The latter non-canonical function of EZH2 partly explains why the current existing enzymatic inhibitors of EZH2 have rather limited antitumor effect. In this project, we aim to employ the Proteolysis Targeting Chimera (PROTAC) technology to develop novel pharmacological ‘degraders’ for depleting EZH2 functions in cancer as a new and more effective therapeutic agent. We have generated highly promising preliminary results showing that, compared to the EZH2 enzymatic inhibitor, our lead E3 ligase-based EZH2-targeting PROTAC (aka EZH2 degrader) efficiently induced depletion of EZH2, thereby suppressing both canonical (PRC2-dependent) and non-canonical (PRC2- independent) activities of EZH2 in tumor. The EZH2 degrader also displays a much stronger potency in killing the aggressive MLL-r AML cells in vitro. Additionally, preliminary characterization of this lead compound revealed an excellent drug-like potential in mice. In this project, I will further (i) determine the effect and potency of our EZH2 degrader in suppressing tumor growth in vivo by using the genetically engineered mouse model (GEMM) and human patient-derived xenograft (PDX) models of MLL-r leukemias (Aim 1) and (ii) define its molecular effects in the MLL-r leukemia cells, focusing on both canonical and non-canonical functions of EZH2, by using the integrated genomic profiling technologies (Aim 2). Results from this project will reveal a promising preclinical strategy for the treatment of human cancers showing EZH2 dependency. Recent FDA approval of compounds targeting epigenetic proteins makes a strong argument.

项目摘要和摘要 Zeste同源2（EZH2）的增强子，Polycomb抑制复合物2（PRC2）的催化亚基，影响 组蛋白H3赖氨酸27（H3K27ME3）的三甲基化用于抑制靶基因表达。许多研究 已经报道EZH2促进了一系列人类癌症的肿瘤发生。特别是独立研究 已经证明EZH2的表达对于急性白血病的肿瘤性至关重要 谱系白血病基因重排（MLL-R），约占基础设施的60–80％ 成人急性淋巴细胞白血病（所有）病例的〜10％，婴儿急性的约50％和约7％ 髓样白血病（AML）病例。 MLL-R患者的白血病患者通常在诊所的预后较差， 要求新的治疗策略。但是，包括我们在内的越来越多的证据支持EZH2 致癌功能超出了PRC2及其在H3K27me3沉积中的酶促功能，并且具有新的，并且具有新的， prc2独立的活性（非规范）来维持肿瘤发生。 EZH2的后一种非典型功能 部分解释了为什么当前现有的EZH2酶抑制剂具有有限的抗肿瘤作用。在这个 项目，我们旨在采用靶向嵌合体（Protac）技术的蛋白水解来开发新颖的 用于耗尽ezh2在癌症中耗尽的药理学“降解者”作为一种新的，更有效的 治疗剂。我们产生了高度有希望的初步结果，表明与EZH2相比 酶促抑制剂，我们的铅E3连接酶基于EZH2靶向Protac（又名EZH2降解器）有效诱导 EZH2的耗竭，从而抑制了规范（依赖PRC2）和非典型的（PRC2-） 独立于EZH2在肿瘤中的活性。 EZH2 DEGRADER还表现出更强的杀戮效力 侵袭性的MLL-R AML细胞体外。此外，该铅化合物的初步表征揭示了 在小鼠中具有出色的药物样潜力。在这个项目中，我将进一步确定我们的效果和效力 通过使用一般工程的小鼠模型（GEMM），EZH2降解器抑制体内肿瘤生长 MLL-R白血病（AIM 1）和（ii）定义其分子 MLL-R-R白血病细胞的影响，重点是EZH2的规范和非规范功能 综合基因组分析技术（AIM 2）。该项目的结果将揭示一个有希望的临床前 治疗人类癌症的策略表现出EZH2依赖性。 FDA最近批准化合物 靶向表观遗传蛋白有很大的论点。