Allosteric Modulators of Polycomb Repressive 2 Gene Repression as Potential Therapeutics for the Development of Novel Epigenetic Cancer Therapies

Polycomb 抑制 2 基因抑制的变构调节剂作为开发新型表观遗传癌症疗法的潜在疗法

• 批准号: 10377438
• 负责人: Guillermo Gerona-Navarro
• 金额: $ 39.25万
• 依托单位: BROOKLYN COLLEGE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10377438
• 关键词: Address; Alanine; Amino Acids; Antineoplastic Agents; Architecture; B-Cell Lymphomas; Binding; Biological Assay; Cancer cell line; Catalytic Domain; Cell Line; Cell Proliferation; Cells; Chemicals; Chromatin; Clear cell renal cell carcinoma; Clinic; Clinical Data; Complex; Data; Development; Disease; Dose; Drug resistance; EZH2 gene; Epigenetic Process; Family; Funding; Future; Gene Expression; Gene Silencing; Genetic Diseases; Genetic Transcription; Goals; Grant; Health; Histones; Human; Hyperactivity; Impairment; Intervention; Invaded; Knowledge; Laboratories; Lead; Link; Lysine; Malignant Epithelial Cell; Malignant Neoplasms; Measures; Metastatic Renal Cell Cancer; Methylation; Modification; Molecular; Mus; Oncology; Patients; Permeability; Polycomb; Preparation; Proliferating; Proteins; Quality of life; Recurrence; Regulator Genes; Renal carcinoma; Reporting; Repression; Research; Research Project Grants; Resistance; Resistance profile; Role; SET Domain; Scanning; Secondary to; Side; Solid; Structure-Activity Relationship; Therapeutic; Tumor Suppressor Genes; Validation; Xenograft Model; alternative treatment; amino group; analog; cancer cell; cancer therapy; carcinogenesis; chemotherapeutic agent; chemotherapy; clinical development; college; design; efficacy evaluation; experimental study; gain of function mutation; gene repression; histone methyltransferase; improved; in vivo; inhibitor; insight; interest; member; molecular dynamics; molecular targeted therapies; mortality; mutant; novel; overexpression; programs; protein complex; stapled peptide; therapeutic development; thioether; tumor; tumorigenesis

Novel and effective anticancer therapies are still of great need since they hold the potential for lower mortality rates, reoccurrence and better quality of life for patients. Cancer is a genetic disease, but its development also involves multiple epigenetic alterations. Epigenetics regulates transcription by modulating chromatin architecture through different mechanisms. Hence, dysregulation of such mechanisms can result in aberrant gene expression or silencing, which in turn can lead to carcinogenesis. One of the most relevant epigenetic modifications is the methylation of lysine 27 at histone 3 (H3K27), a broadly known repressive histone mark. H3K27 methylation is incorporated by the polycomb repressive complex 2 (PRC2), a multimeric protein complex formed by four core components: EZH2, EED, SUZ12 and RbAp46/48, all of which are essential for its catalytic activity. Overexpression of PRC2 proteins, particularly of EZH2, results in hyperactivation of the complex and high levels of H3K27m3, which are associated to a myriad of human cancers. Several PRC2 inhibitors have been discovered to date, some which are currently in clinical development. These compounds target either the catalytic SET domain of EZH2 or EED allosterically. Although they have delivered some promising results, recent reports indicate that extended dosing with them leads to secondary EZH2 mutants that become resistant to treatment. Hence, novel inhibitors of PRC2 function are of great interest, since such compounds could offer an alternative solution to address the above-mentioned resistant profiles. Recently, our laboratory has reported the discovery of a potent, cell permeable stapled peptide, GN-ZW11, as a potent and selective inhibitor of H3K27me3 in renal carcinoma cells. This compound was designed to target the SANT2 domain in EZH2, and thus it may well be the first-in class EZH2 allosteric inhibitor described to date. The current proposal aims to expand our preliminary studies with GN-ZW11 by carrying out, first, structural-activity relationship studies to understand the molecular determinants of its binding, as well as to gather valuable data for the design of GN-ZW11 analogs with improved potency and stability. Secondly, we propose to carry out further biological assays in metastatic renal carcinoma cells to better understand the mechanism of action of GN-ZW11 and to evaluate its therapeutic potential for the treatment of clear cell renal cell carcinoma. Finally, we plan on expanding our preliminary studies to other cancer cell lines in which PRC2 proteins have been found overexpressed and to investigate the impact of PRC2 inhibition by GN-ZW11 in vivo, by measuring its ability to induce tumor regression in mouse xenografts models. In summary, the proposed research project will result in the preparation and validation of a new family of allosteric inhibitors of PRC2 function. We expect that the knowledge gained from these studies will help to improve our overall understanding surrounding the role of EZH2 in oncology, and will also guide the identification of targeted chemotherapeutics for treating humans in the future.

新颖有效的抗癌疗法仍然非常需要，因为它们具有降低死亡率的潜力 患者的发生率，再发生和更好的生活质量。癌症是一种遗传疾病，但它的发展也 涉及多种表观遗传改变。表观遗传学通过调节染色质调节转录 通过不同的机制进行体系结构。因此，这种机制的失调可能导致异常 基因表达或沉默，这又会导致致癌。最相关的表观遗传之一 修饰是组蛋白3（H3K27）的赖氨酸27的甲基化，这是一种广泛已知的抑制性组蛋白标记。 H3K27甲基化由Polycomb抑制复合物2（PRC2）（一种多聚体蛋白）掺入 由四个核心组成部分形成的复合物：EZH2，EED，SUZ12和RBAP46/48，所有这些都对 它的催化活性。 PRC2蛋白的过表达，特别是EZH2的过表达，导致过度激活 复杂且高水平的H3K27M3与无数人类癌症有关。几个Prc2 迄今已发现抑制剂，其中一些目前正在临床开发中。 这些化合物 靶向EZH2的催化集域或EED变构。尽管他们已经交付了一些 有希望的结果，最近的报告表明，与它们的延长给药导致了次级EZH2突变体 那变得对治疗具有抵抗力。因此，新型PRC2功能的抑制剂引起了极大的兴趣，因为这样 化合物可以提供 一种解决上述抗性轮廓的替代解决方案。最近，我们的 实验室报告了发现有效的，可渗透的钉钉肽， GN-ZW11，作为有效的 肾癌细胞中H3K27me3的选择性抑制剂。该化合物旨在靶向sant2 EZH2中的域，因此很可能是迄今为止描述的第一类EZH2抑制剂。这 当前的建议旨在通过首先，结构活动来扩大我们的初步研究 关系研究以了解其结合的分子决定因素，并收集有价值的数据 为了设计具有提高效力和稳定性的GN-ZW11类似物。其次，我们建议进行 转移性肾癌细胞中的进一步生物学测定，以更好地了解 GN-ZW11并评估其治疗透明细胞肾细胞癌的治疗潜力。最后， 我们计划将初步研究扩展到其他癌细胞系，其中Prc2蛋白已成为 发现过表达并研究gn-ZW11在体内抑制PRC2的影响 在小鼠异种移植模型中诱导肿瘤消退的能力。总而言之，拟议的研究项目将 导致PRC2功能变构抑制剂的新家族的准备和验证。我们期望这一点 从这些研究中获得的知识将有助于提高我们围绕的作用的整体理解 肿瘤学中的EZH2，还将指导鉴定有针对性的化学治疗剂用于治疗人类 未来。