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: 10387358
• 负责人: A-Rum Kim
• 金额: $ 7.17万
• 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 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10387358
• 关键词: Acute Myelocytic Leukemia; Acute leukemia; Adult Acute Lymphocytic Leukemia; Adult Acute Myeloblastic Leukemia; Antineoplastic Agents; Biology; CCNE1 gene; Cancer Biology; Cancer Patient; Catalytic Domain; Cells; Chemicals; Chromatin; Clinic; Clinical; 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; Pharmacology; Pharmacotherapy; Polycomb; Positioning Attribute; Prognosis; Protac; Proteins; Publishing; Regimen; Regulator Genes; Reporting; Research Personnel; Role; Site; Technology; Therapeutic Agents; Therapeutic Effect; Training; Tumorigenicity; acute myeloid leukemia cell; anti-cancer; antitumor effect; base; cancer therapy; cell growth; clinical application; design; gene repression; 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; 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（EZH 2）的增强子，多梳抑制复合物2（PRC 2）的催化亚基，诱导 组蛋白H3赖氨酸27（H3 K27 me 3）的三甲基化以抑制靶基因表达。大量研究 已经报道了EZH 2在一系列人类癌症中促进肿瘤发生。特别是独立研究 已经证明EZH 2的表达对于急性白血病的致瘤性是必需的， 谱系白血病基因重排（MLL-r），占婴儿和新生儿白血病的约60-80%， 约10%的成人急性淋巴细胞白血病（ALL）病例，约50%的婴儿和约7%的成人急性淋巴细胞白血病（ALL）病例 骨髓性白血病（AML）病例。具有MLL-r的白血病患者在临床上通常表现出非常差的预后， 需要新的治疗策略。然而，包括我们在内的越来越多的证据支持EZH 2 致癌功能超越了PRC 2及其对H3 K27 me 3沉积的酶功能，并具有新的， PRC 2独立活性（非典型），以维持肿瘤发生。EZH 2的后一个非正则函数 部分解释了为什么目前存在的EZH 2酶抑制剂具有相当有限的抗肿瘤作用。在这 项目，我们的目标是采用蛋白水解靶向嵌合体（PROTAC）技术，开发新的 作为一种新的更有效的药物“降解剂”，用于消除癌症中的EZH 2功能 治疗剂我们已经产生了非常有希望的初步结果表明，与EZH 2相比， 酶抑制剂，我们领先的基于E3连接酶的EZH 2靶向PROTAC（又名EZH 2降解剂）有效诱导 EZH 2的耗尽，从而抑制典型（PRC 2依赖性）和非典型（PRC 2依赖性）两者。 EZH 2在肿瘤中的活性。EZH 2降解剂还显示出更强的杀伤力， 在体外的侵袭性MLL-r AML细胞。此外，这种先导化合物的初步表征显示， 在小鼠中具有良好的药物样潜力。在这个项目中，我将进一步（i）确定我们的效果和效力 EZH 2降解剂通过使用基因工程小鼠模型（GEMM）在体内抑制肿瘤生长 和人患者来源的MLL-r白血病异种移植物（PDX）模型（Aim 1）和（ii）定义其分子生物学特性， 在MLL-r白血病细胞中的作用，集中于EZH 2的典型和非典型功能，通过使用 整合基因组分析技术（目标2）。该项目的结果将揭示一个有前途的临床前 用于治疗显示EZH 2依赖性的人类癌症的策略。最近FDA批准的化合物 以表观遗传蛋白为靶点是一个有力的论据。