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.

项目概要和摘要 Zeste 同源物 2 (EZH2) 的增强剂是 Polycomb 抑制复合物 2 (PRC2) 的催化亚基，可诱导 组蛋白 H3 赖氨酸 27 (H3K27me3) 的三甲基化可抑制靶基因表达。大量研究 据报道，EZH2 促进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致瘤性至关重要 谱系白血病基因重排 (MLL-r)，约占婴儿和儿童白血病的 60-80% 约 10% 的成人急性淋巴细胞白血病 (ALL) 病例，以及约 50% 的婴儿病例和约 7% 的成人急性淋巴细胞白血病病例 骨髓性白血病（AML）病例。 MLL-r的白血病患者在临床上通常表现出非常差的预后， 要求新的治疗策略。然而，包括我们在内的越来越多的证据现在支持 EZH2 致癌功能超越了 PRC2 及其 H3K27me3 沉积的酶功能，并且具有新的、 PRC2 独立活性（非规范）维持肿瘤发生。 EZH2 的后一个非规范函数 这部分解释了为什么目前现有的EZH2酶抑制剂的抗肿瘤作用相当有限。在这个 项目中，我们的目标是利用蛋白水解靶向嵌合体（PROTAC）技术来开发新型 消除癌症中 EZH2 功能的药理学“降解剂”是一种新的更有效的方法 治疗剂。我们已经得出了非常有希望的初步结果，表明与 EZH2 相比 酶抑制剂，我们的主要基于 E3 连接酶的 EZH2 靶向 PROTAC（又名 EZH2 降解剂）有效诱导 EZH2 的耗尽，从而抑制规范（PRC2 依赖）和非规范（PRC2- EZH2 在肿瘤中的独立）活性。 EZH2 降解剂还表现出更强的杀灭能力 体外侵袭性 MLL-r AML 细胞。此外，该先导化合物的初步表征表明 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（i）确定我们的效果和效力 EZH2 降解剂通过使用基因工程小鼠模型 (GEMM) 抑制体内肿瘤生长 和人类患者来源的 MLL-r 白血病异种移植 (PDX) 模型（目标 1）和 (ii) 定义其分子 通过使用 EZH2 的规范和非规范功能，对 MLL-r 白血病细胞的影响 综合基因组分析技术（目标 2）。该项目的结果将揭示一个有前途的临床前 治疗表现出 EZH2 依赖性的人类癌症的策略。 FDA 最近批准了化合物 针对表观遗传蛋白提出了强有力的论据。