EZH2 in cancer biology and novel inhibitors

EZH2 在癌症生物学和新型抑制剂中的应用

基本信息

批准号：
10453696
负责人：
Jun QI
金额：
$ 52.85万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10453696
关键词：
Adenosine Animal Model Automobile Driving B-Cell Lymphomas B-Lymphocytes Binding Biological Biology Bromodomain Cancer Biology Cancer Cell Growth Cancer cell line Cell Culture Techniques Cells Chemicals Chemistry Chromatin Chromatin Structure Clinical Trials Complex Computer Models Cysteine Development Enhancers Environment Epigenetic Process Epithelial Event Gene Activation Gene Expression Genes Genetic Genetic Transcription Hematologic Neoplasms Heterochromatin Histone Deacetylase Histones Human Immune In Vitro Joints Lead Legal patent Link Lung Lung Adenocarcinoma Lymphoma Lysine Maintenance Malignant Neoplasms Malignant neoplasm of lung Methionine Methylation Modeling Mus Mutate Nature Normal Cell Organoids Pathogenesis Patients Penetrance Pharmaceutical Chemistry Pharmacology Polycomb Population Post-Translational Protein Processing Prognosis Property Proteins Publications Qi Reagent Recurrence Repression Research Role S-Adenosylhomocysteine Scientist Signal Pathway Solid Somatic Mutation T-Cell Leukemia Therapeutic Therapeutic Agents Therapeutic Trials Toxic effect Transferase Translations Work anti-cancer cancer cell cancer genetics cancer therapy carcinogenesis cell type clinical candidate clinical investigation cofactor experience gain of function genetic regulatory protein histone methylation histone modification immunoregulation improved in vivo inhibitor innovation insight interest lead optimization loss of function melanocyte melanoma mouse model mutant new therapeutic target novel novel therapeutic intervention novel therapeutics overexpression preclinical study prevent protein complex recruit refractory cancer scaffold small molecule small molecule inhibitor success targeted cancer therapy translational potential tumor tumor growth tumor microenvironment tumor-immune system interactions

项目摘要

Enhancer of zeste 2 (EZH2), a histone methyl transferase subunit of the Polycomb Repressive Complex 2 (PRC2), catalyzes the methylation of lysine residue 27 on histone 3 (H3K27). Methylation of H3K27 inhibits the transcription of nearby genes by blocking the recruitment of the proteins necessary for gene activation. The PRC2 complex and the histone modifications that it regulates are tightly controlled in normal cells but can become dysregulated in cancer to aberrantly activate or repress gene expression. Over the last decade, many independent studies have established that EZH2 is highly expressed in numerous cancers and recurrently mutated in several others. Overexpression of EZH2 is associated with aggressive progression and poor prognosis. We recently demonstrated that overexpression of EZH2 is causative of lung adenocarcinoma in mice. Likewise, activating somatic mutations of EZH2 have been identified in B cell lymphoma and malignant melanoma. We developed mouse models to express the gain-of-function mutant of EZH2 in B cells or melanocytes, which caused high-penetrance lymphoma or melanoma, respectively. Our studies with mouse models that express the gain-of-function mutant of EZH2 suggest that EZH2Y641F induces lymphoma and melanoma through a vast reorganization of chromatin structure inducing both repression and activation of PRC2-regulated loci. The extensive evidence linking EZH2 activity to cancer has prompted interest in the underlying biological mechanisms, including the link to the tumor immune environment. As such, we developed a novel EZH2 small molecule inhibitor, JQEZ5, that can efficiently block the enzymatic function of both wild-type and mutant EZH2 and reduce the methylation of H3K27. The inhibitory activity of JQEZ5 impedes the growth of cancer cells in culture and in mouse models of lung cancer, lymphoma and melanoma. Mechanistically, JQEZ5 is a non-covalent inhibitor that competes off natural co-factor S-adenosine methionine (SAM) from binding with EZH2. The SAM-competitive nature of all current EZH2 inhibitors largely limited their in vivo potency, which could potentially limit their usage in cancer therapy. To improve the in vivo efficacy of EZH2 inhibitors and reduce off-target toxicity, we propose to develop and characterize a new class of covalent EZH2 inhibitors that can irreversibly bind to unique cysteine residue (C663) present in human and mouse EZH2. We hypothesize that the irreversible biding of this new class inhibitors can overcome key limitations of the existing non-covalent inhibitors, and improve in vivo potency and selectivity. We will employ the new covalent EZH2 inhibitors to further investigate cancer biology of EZH2 inhibition in lung cancer, including the immunomodulatory effects of EZH2 inhibition. We will utilize our cell culture and mouse models of EZH2-driven cancer to explore the impact of irreversible inhibition of EZH2 on gene expression and the tumor immune microenvironment while driving hit-to-lead optimization of covalent EZH2 inhibitors that can prompt clinical investigation to fully explore the translational potential of EZH2 inhibitors.

Zeste 2（EZH2）的增强子，一种组蛋白甲基转移酶亚基Polycomb抑制络合物2 （PRC2），催化组蛋白3（H3K27）上赖氨酸残基27的甲基化。 H3K27的甲基化抑制通过阻断基因激活所需的蛋白质的募集来对附近基因的转录。这 PRC2复合物和调节的组蛋白修饰在正常细胞中受到严格控制，但可以在癌症中失调，异常激活或抑制基因表达。在过去的十年中，许多独立研究已经确定EZH2在许多癌症中高度表达，并经常反复表达在其他几个人中发生突变。 EZH2的过表达与侵略性进展和差有关预后。我们最近证明了EZH2的过表达是肺腺癌的原因老鼠。同样，在B细胞淋巴瘤和恶性肿瘤中已经鉴定出EZH2的体细胞突变黑色素瘤。我们开发了小鼠模型，以表达B细胞中EZH2的功能收益突变体或黑色素细胞分别引起高渗透淋巴瘤或黑色素瘤。我们对老鼠的研究表达EZH2功能收益突变体的模型表明EZH2Y641F诱导淋巴瘤和黑色素瘤通过染色质结构的广泛重组，诱导抑制和激活 PRC2调节的基因座。将EZH2活动与癌症联系起来的广泛证据引起了人们对基本的生物学机制，包括与肿瘤免疫环境的联系。因此，我们开发了一种新型的EZH2小分子抑制剂JQEZ5，可以有效地阻断酶促的野生型和突变体EZH2的功能，并降低H3K27的甲基化。的抑制活性 JQEZ5阻碍了培养和肺癌，淋巴瘤和小鼠模型中癌细胞的生长黑色素瘤。从机械上讲，JQEZ5是一种非共价抑制剂，它可以在天然co-Faltor S-腺苷上竞争与EZH2结合的蛋氨酸（SAM）。所有当前EZH2抑制剂的SAM竞争性质很大限制其体内效力，这可能会限制其在癌症治疗中的使用。为了提高EZH2抑制剂的体内功效并降低脱靶毒性，我们建议开发和表征一类新的共价ezh2抑制剂，可以不可逆地结合独特的半胱氨酸残基（C663）存在于人和老鼠EZH2中。我们假设这个新类抑制剂的不可逆转的竞标可以克服现有非共价抑制剂的关键局限性，并提高体内效力和选择性。我们将采用新的共价EZH2抑制剂来进一步研究肺中EZH2抑制的癌症生物学癌症，包括EZH2抑制的免疫调节作用。我们将利用我们的细胞培养和鼠标 EZH2驱动的癌症模型探讨了对EZH2对基因表达和肿瘤免疫微环境在驱动可击中的EZH2抑制剂的命中率优化时迅速进行临床研究，以充分探索EZH2抑制剂的翻译潜力。