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.

新的和有效的抗癌疗法仍然是非常需要的，因为它们具有降低死亡率的潜力 率，复发率和更好的患者生活质量。癌症是一种遗传性疾病，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来调节转录 通过不同的机制。因此，这些机制的失调可导致异常的免疫应答。 基因表达或沉默，这反过来又会导致致癌作用。其中一个最相关的表观遗传 修饰是组蛋白3（H3 K27）处赖氨酸27的甲基化，这是一种广为人知的抑制性组蛋白标记。 H3 K27甲基化通过多梳抑制复合物2（PRC 2）（一种多聚体蛋白）并入 由四个核心组件组成的复合体：EZH 2、EED、SUZ 12和RbAp 46/48，所有这些都是必不可少的 其催化活性。PRC 2蛋白，特别是EZH 2的过表达，会导致细胞内蛋白的过度活化。 复杂和高水平的H3 K27 m3，这与无数的人类癌症。几个PRC 2 迄今为止已经发现了一些抑制剂，其中一些目前正在临床开发中。 这些化合物 变构地靶向EZH 2或EED的催化SET结构域。虽然他们已经交付了一些 有希望的结果，最近的报告表明，延长剂量与他们导致二次EZH 2突变体 对治疗产生抗药性。因此，PRC 2功能的新型抑制剂是非常令人感兴趣的，因为这类抑制剂具有更高的活性。 化合物可以提供 一种解决上述耐腐蚀特性的替代方案。最近我们 实验室已经报道了一种有效的、细胞可渗透的钉合肽的发现， GN-ZW 11作为一种有效的 H3 K27 me 3的选择性抑制剂。这种化合物被设计成靶向SANT 2 因此，它很可能是迄今为止描述的第一类EZH 2变构抑制剂。的 目前的建议旨在通过首先进行结构活性来扩展我们对GN-ZW 11的初步研究 关系研究，以了解其结合的分子决定因素，以及收集有价值的数据 用于设计具有改进的效力和稳定性的GN-ZW 11类似物。第二，我们建议推行 在转移性肾癌细胞中进行进一步的生物学测定，以更好地了解 GN-ZW 11，并评估其治疗肾透明细胞癌的治疗潜力。最后， 我们计划将我们的初步研究扩展到其他癌细胞系，其中PRC 2蛋白已经被 发现PRC 2过表达，并通过测量其表达水平来研究GN-ZW 11在体内对PRC 2抑制的影响。 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PRC 2功能的变构抑制剂的新家族的制备和验证。我们预计 从这些研究中获得的知识将有助于提高我们对以下问题的全面理解： EZH 2在肿瘤学中的应用，也将指导用于治疗人类肿瘤的靶向化疗药物的鉴定。 未来