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，cambinol是一种人nad依赖性去乙酰化酶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依赖的去乙酰化酶参与了细胞对应激反应的控制，并通过p53和BCL6癌蛋白等重要调节蛋白的去乙酰化参与了肿瘤发生。我们已经发现了一种我们命名为cambinol的化合物，它可以抑制人类SIRT1和SIRT2的nadd依赖性去乙酰化酶活性。与SIRT1在应激条件下促进细胞存活的作用一致，在基因毒性应激条件下，cambinol抑制SIRT1活性会导致关键应激反应蛋白的超乙酰化，并促进细胞周期阻滞。cambinol单药治疗表达BCL6的Burkitt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的超乙酰化。由于乙酰化使BCL6失活并激活p53等检查点通路，因此，cambinol在BL细胞中的抗肿瘤活性可能是由于BCL6失活和检查点激活的共同作用。在初步研究中，cambinol在小鼠中具有良好的耐受性，并能抑制BL异种移植物的生长。生发中心是b细胞在发生体细胞超突变和类开关重组过程中迅速增殖的发育阶段。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）作为蛋白去乙酰化酶的已知作用，我们假设SIRT1和/或SIRT2控制生发中心b细胞中可用于治疗淋巴瘤的基本转录程序。我们将在一个聚合研究项目中检验这一假设。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作为生发中心源性淋巴瘤的抗癌药物靶点。生发中心的形成将作为b细胞淋巴瘤形成的替代物；3）. 确定SIRT1/2介导的BCL6去乙酰化在cambinol抗淋巴瘤活性中的作用；4）. 利用人淋巴瘤异种移植小鼠和转基因小鼠DLBC淋巴瘤模型，测定优化后的SIRT1/2抑制剂在体内的活性。这些跨学科的研究将为nad依赖性去乙酰化酶作为可行的抗癌药物靶点提供关键的验证。公共卫生相关性：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和细胞分化的酶。细胞分化的失调导致了几乎所有淋巴瘤的发展。我们的初步数据表明，SIRT1和SIRT2的抑制对B细胞淋巴瘤细胞是致命的，并使许多其他类型的癌细胞对应激条件（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和选择性的SIRT1抑制剂作为抗淋巴瘤药物。