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: 8230766
• 负责人: Antonio Bedalov
• 金额: $ 35.42万
• 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 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8230766
• 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; Genomic Instability; Genotoxic Stress; Goals; Growth; Health; 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; 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; 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）：该提案的目的是综合和评估cambinol的类似物，cambinol是人类NAD NAD依赖性脱乙酰基酶SIRT1和SIRT2的小分子抑制剂，并验证SIRT1和/或SIRT2作为渗透中心淋巴瘤的治疗靶标的SIRT1和/或SIRT2。 SIRT1，SIRT2和其他NAD依赖性脱乙酰基酶与通过脱乙酰化（包括p53和Bcl6癌蛋白）的脱乙酰化来控制对压力的反应和肿瘤发生。我们已经确定了一种我们命名的化合物，该化合物抑制了人类SIRT1和SIRT2的NAD依赖性脱乙酰基酶活性。与SIRT1在促进胁迫期间促进细胞存活中的作用一致，在遗传毒性应激过程中抑制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。 Bcl6-表达Burkitt淋巴瘤（BL）和弥漫性大B细胞淋巴瘤（DLBCL）细胞用cambinol作为单一药物诱导凋亡，并伴有Bcl6和p53的高乙酰化。由于乙酰化会使BCL6失活并激活p53和其他检查点途径，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在小鼠中的耐受性良好，并抑制了BL异种移植的生长。生发中心是一个发育阶段，当B细胞在经历体细胞超成名和类转换重组的同时快速增殖。尽管基因组不稳定性，生发中心细胞的快速增殖是通过通过BCl6依赖性和其他转录抑制机制抑制DNA破坏检查点来完成的。基于SIRT1和SIRT2（SIRT1/2）作为蛋白质脱乙酰基酶的已知作用，其作用于许多靶标，我们假设SIRT1和/或SIRT2控制了可以利用用于治疗淋巴瘤的生发中心B细胞中基本的转录程序。我们将在收敛研究计划中检验这一假设。我们将：1）开发cambinol的同工型特异性类似物，并为SIRT1和SIRT2同工型抑制剂组装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标。生发中心的形成将作为B细胞淋巴作用的替代物。 3）。确定SIRT1/2-介导的Bcl6介导的脱乙酰基化在剑BINOL抗肾小球活性中的作用，并且； 4）。使用小鼠和DLBC淋巴瘤的转基因小鼠模型中的人体淋巴瘤异种移植物在体内优化的SIRT1/2抑制剂的活性。这些跨学科研究将为NAD依赖性脱乙酰基酶作为可行的抗癌药物靶标提供关键的验证。 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，该药物是一种涉及调节细胞对压力和细胞分化的反应的酶。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和SIRT2对B-细胞淋巴瘤细胞具有致命性，并使许多其他癌细胞类型敏感到诸如标准细胞毒性化学疗法之类的压力状况。我们的目标是使用药物化学，蛋白质晶体学，生物化学和细胞生物学的工具来开发SIRT1作为抗淋巴瘤药物的有效和选择性抑制剂。

项目成果

Absence of effects of Sir2 overexpression on lifespan in C. elegans and Drosophila.

• DOI: 10.1038/nature10296
• 发表时间: 2011-09-21
• 期刊: NATURE
• 影响因子: 64.8
• 作者: Burnett, Camilla;Valentini, Sara;Cabreiro, Filipe;Goss, Martin;Somogyvari, Milan;Piper, Matthew D.;Hoddinott, Matthew;Sutphin, George L.;Leko, Vid;McElwee, Joshua J.;Vazquez-Manrique, Rafael P.;Orfila, Anne-Marie;Ackerman, Daniel;Au, Catherine;Vinti, Giovanna;Riesen, Michele;Howard, Ken;Neri, Christian;Bedalov, Antonio;Kaeberlein, Matt;Soti, Csaba;Partridge, Linda;Gems, David
• 通讯作者: Gems, David

Development of pyrazolone and isoxazol-5-one cambinol analogues as sirtuin inhibitors.

• DOI: 10.1021/jm4018064
• 发表时间: 2014-04-24
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: Mahajan SS;Scian M;Sripathy S;Posakony J;Lao U;Loe TK;Leko V;Thalhofer A;Schuler AD;Bedalov A;Simon JA
• 通讯作者: Simon JA

Identification of inhibitors of chromatin modifying enzymes using the yeast phenotypic screens.

使用酵母表型筛选鉴定染色质修饰酶抑制剂。

• DOI: 10.1007/978-1-59745-540-4_8
• 发表时间: 2009
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Newcomb,Benjamin;Bedalov,Antonio
• 通讯作者: Bedalov,Antonio

Sirtuin modulators.

• DOI: 10.1007/978-3-642-21631-2_11
• 发表时间: 2011-01-01
• 期刊: Handbook of experimental pharmacology
• 作者: Mahajan, Sumit S;Leko, Vid;Bedalov, Antonio
• 通讯作者: Bedalov, Antonio

SIRT1 promotes N-Myc oncogenesis through a positive feedback loop involving the effects of MKP3 and ERK on N-Myc protein stability.

• DOI: 10.1371/journal.pgen.1002135
• 发表时间: 2011-06
• 期刊: PLoS genetics
• 影响因子: 4.5
• 作者: Marshall GM;Liu PY;Gherardi S;Scarlett CJ;Bedalov A;Xu N;Iraci N;Valli E;Ling D;Thomas W;van Bekkum M;Sekyere E;Jankowski K;Trahair T;Mackenzie KL;Haber M;Norris MD;Biankin AV;Perini G;Liu T
• 通讯作者: Liu T