Development of cambinol analogues as antilymphoma agents

作为抗淋巴瘤药物的 Cambinol 类似物的开发

• 批准号: 7768411
• 负责人: Antonio Bedalov
• 金额: $ 36.52万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7768411
• 关键词: Acetylation; Animals; Antineoplastic Agents; Apoptosis; B cell differentiation; B-Cell Lymphomas; B-Lymphocytes; BCL6 gene; Biochemistry; Biological Assay; Burkitt Lymphoma; Cell Cycle Arrest; Cell Survival; Cells; Cellular biology; Chromatin; Crystallography; Cytotoxic Chemotherapy; DNA damage checkpoint; Data; Deacetylase; Deacetylation; Development; Drug Delivery Systems; Enzymes; Evaluation; Face; Genomic Instability; Genotoxic Stress; Goals; Growth; Homologous Gene; Human; Human Activities; Immunoglobulin Class Switching; Immunoglobulin Somatic Hypermutation; Immunoglobulin Switch Recombination; In Vitro; Interdisciplinary Study; Lead; Lymphoma; Lymphomagenesis; Maintenance; Malignant Neoplasms; Mediating; Mediator of activation protein; Mus; Names; Non-Malignant; Oncogene Proteins; Pathway interactions; Pharmaceutical Chemistry; Pharmaceutical Preparations; Play; Process; Proliferating; Protein Isoforms; Proteins; Regulation; Research; Role; Series; Specificity; Staging; Stress; Structure of germinal center of lymph node; TP53 gene; Testing; Therapeutic Agents; Transgenic Mice; Validation; Xenograft procedure; Yeasts; analog; base; biological adaptation to stress; cancer cell; cell type; chemical genetics; drug development; gene repression; genetic regulatory protein; human disease; in vivo; inhibitor/antagonist; large cell Diffuse non-Hodgkin' s lymphoma; mouse model; programs; public health relevance; response; small molecule; splitomicin; therapeutic target; tool; tumorigenesis

DESCRIPTION (provided by applicant): The goal of this proposal is to synthesize and evaluate analogues of cambinol, a small molecule inhibitor of human NAD-dependent deacetylases SIRT1 and SIRT2, and to validate SIRT1 and/or SIRT2 as therapeutic targets in germinal center lymphomas. SIRT1, SIRT2 and other NAD- dependent deacetylases have been implicated in control of cellular responses to stress and in tumorigenesis through deacetylation of important regulatory proteins including p53 and the BCL6 oncoprotein. We have identified a compound we named cambinol that inhibits NAD-dependent deacetylase activity of human SIRT1 and SIRT2. Consistent with the role of SIRT1 in promoting cell survival during stress, inhibition of SIRT1 activity with cambinol during genotoxic stress leads to hyperacetylation of key stress response proteins and promotes cell cycle arrest. Treatment of BCL6- expressing Burkitt's lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL) cells with cambinol as a single agent induces apoptosis and is accompanied by hyperacetylation of BCL6 and p53. Because acetylation inactivates BCL6 and activates p53 and other checkpoint pathways, the antitumor activity of cambinol in BL cells may be due to a combined effect of BCL6 inactivation and checkpoint activation. In preliminary studies, cambinol was well tolerated in mice and inhibited growth of BL xenografts. Germinal center is a developmental stage when B-cells proliferate rapidly while undergoing somatic hypermutation and class switch recombination. Rapid proliferation of germinal center cells in spite of genomic instability is accomplished in part through suppression of DNA-damage checkpoints through BCL6-dependent and other transcriptional repression mechanisms. Based on the known roles of SIRT1 and SIRT2 (SIRT1/2) as protein deacetylases that act on a number of targets, we hypothesize that SIRT1 and/or SIRT2 controls essential transcriptional programs in germinal center B-cells that can be exploited for treatment of lymphoma. We will test this hypothesis in a convergent research program. We will: 1) Develop isoform specific analogues of cambinol and assemble an SAR for SIRT1 and SIRT2 isoform specific inhibitors; 2). Validate SIRT1 and/or SIRT2 as anticancer drug targets for germinal center-derived lymphomas. Germinal center formation will serve as a surrogate for B-cell lymphomagenesis; 3). Determine the role of SIRT1/2- mediated deacetylation of BCL6 in cambinol's antilymphoma activity, and; 4). Determine the activity of optimized SIRT1/2 inhibitors in vivo using human lymphoma xenografts in mice and in the transgenic mouse model of DLBC lymphomas. These interdisciplinary studies will provide critical validation for NAD-dependent deacetylases as viable anticancer drug targets. PUBLIC HEALTH RELEVANCE: We propose to develop new anti-lymphoma drugs that target SIRT1, an enzyme involved in regulating cells' response to stress as well as cellular differentiation. Deregulation of cellular differentiation leads to the development of almost all lymphomas. Our preliminary data suggest that inhibition of SIRT1 and perhaps SIRT2 is lethal to B- cell lymphoma cells and sensitizes many other cancer cell types to conditions of stress such as standard cytotoxic chemotherapy. Our goal is to use the tools of medicinal chemistry, protein crystallography, biochemistry and cell biology to develop potent and selective inhibitors of SIRT1 as anti-lymphoma drugs.

描述（由申请人提供）：本提案的目标是合成和评估 Cambinol 的类似物（一种人 NAD 依赖性脱乙酰酶 SIRT1 和 SIRT2 的小分子抑制剂），并验证 SIRT1 和/或 SIRT2 作为生发中心淋巴瘤的治疗靶点。 SIRT1、SIRT2 和其他 NAD 依赖性脱乙酰酶通过重要调节蛋白（包括 p53 和 BCL6 癌蛋白）的脱乙酰作用参与细胞对应激反应的控制和肿瘤发生。我们已经鉴定出一种化合物，我们将其命名为 Cambinol，它可以抑制人类 SIRT1 和 SIRT2 的 NAD 依赖性脱乙酰酶活性。与 SIRT1 在应激期间促进细胞存活的作用一致，在基因毒性应激期间用 Cambinol 抑制 SIRT1 活性会导致关键应激反应蛋白的过度乙酰化并促进细胞周期停滞。用cambinol作为单药治疗表达BCL6的伯基特淋巴瘤(BL)和弥漫性大B细胞淋巴瘤(DLBCL)细胞可诱导细胞凋亡，并伴有BCL6和p53的过度乙酰化。由于乙酰化使 BCL6 失活并激活 p53 和其他检查点通路，因此 BL 细胞中 Cambinol 的抗肿瘤活性可能是由于 BCL6 失活和检查点激活的综合作用。在初步研究中，cambinol 在小鼠中具有良好的耐受性并抑制 BL 异种移植物的生长。生发中心是 B 细胞快速增殖并同时经历体细胞超突变和类别转换重组的发育阶段。尽管基因组不稳定，生发中心细胞的快速增殖部分是通过 BCL6 依赖性和其他转录抑制机制抑制 DNA 损伤检查点来实现的。基于 SIRT1 和 SIRT2 (SIRT1/2) 作为作用于许多靶标的蛋白质脱乙酰酶的已知作用，我们假设 SIRT1 和/或 SIRT2 控制生发中心 B 细胞中的重要转录程序，可用于治疗淋巴瘤。我们将在一个聚合研究计划中检验这个假设。我们将： 1) 开发 Cambinol 的异构体特异性类似物，并组装 SIRT1 和 SIRT2 异构体特异性抑制剂的 SAR； 2）。验证 SIRT1 和/或 SIRT2 作为生发中心衍生淋巴瘤的抗癌药物靶点。生发中心的形成将作为 B 细胞淋巴瘤发生的替代指标； 3）。确定 SIRT1/2 介导的 BCL6 脱乙酰化在 Cambinol 抗淋巴瘤活性中的作用； 4）。使用小鼠中的人淋巴瘤异种移植物和 DLBC 淋巴瘤转基因小鼠模型确定优化的 SIRT1/2 抑制剂的体内活性。这些跨学科研究将为 NAD 依赖性脱乙酰酶作为可行的抗癌药物靶点提供关键验证。 公共健康相关性：我们建议开发针对 SIRT1 的新型抗淋巴瘤药物，SIRT1 是一种参与调节细胞对应激反应以及细胞分化的酶。细胞分化的失调导致几乎所有淋巴瘤的发展。我们的初步数据表明，抑制 SIRT1（或许还有 SIRT2）对于 B 细胞淋巴瘤细胞是致命的，并使许多其他癌细胞类型对应激条件（例如标准细​​胞毒性化疗）敏感。我们的目标是利用药物化学、蛋白质晶体学、生物化学和细胞生物学的工具来开发有效的、选择性的 SIRT1 抑制剂作为抗淋巴瘤药物。