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SIRT2 Inhibitors for the Treatment of B-cell Lymphoma

SIRT2 抑制剂用于治疗 B 细胞淋巴瘤

基本信息

批准号：
9197069
负责人：
Antonio Bedalov
金额：
$ 57.33万
依托单位：
FRED HUTCHINSON CANCER RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-07 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9197069
关键词：
Acetylation B-Cell Lymphomas B-Lymphocytes BCL6 gene Biological Markers CREBBP gene Cell Line Cell Maturation Cells Clinical Clinical Trials Cutaneous Data Deacetylase Development Dose Drug Design Drug Targeting EP300 gene Enzymes Equilibrium Exhibits Follicular Lymphoma Frequencies Future Genes Genetic Goals Hematopoietic Neoplasms High Prevalence Histone Deacetylase Inhibitor Histones Human In Vitro Indolent Investigational Drugs Knock-out Knowledge Large-Scale Sequencing Ligand Binding Lymphoma Lymphomagenesis Lysine Malignant Neoplasms Mediator of activation protein Modality Modeling Mus Mutation NMR Spectroscopy Niacinamide Normal Cell Pathogenesis Pathway interactions Patients Pharmaceutical Chemistry Phenotype Physiological Play Property Protein Acetylation Proteins Role Sampling Sirtuins Specimen Structure Structure of germinal center of lymph node Structure-Activity Relationship T-Cell Lymphoma TP53 gene Testing Therapeutic Therapeutic Agents Toxic effect Transcription Repressor/Corepressor Transferase Transgenic Mice Vorinostat Work Xenograft procedure analog base chemotherapeutic agent effective therapy in vitro activity in vivo inhibitor/antagonist knowledge base large cell Diffuse non-Hodgkin&apos s lymphoma loss of function loss of function mutation mouse model mutant neoplastic cell new therapeutic target novel therapeutics pharmacodynamic biomarker programs research study small molecule systemic toxicity therapeutic target treatment strategy tumor tumor growth tumorigenesis

项目摘要

We propose to develop inhibitors of NAD+-dependent deacetylase SIRT2 as new, targeted, non-toxic chemotherapeutic agents that inactivate BCL6, a key driver of tumorigenesis in B-cell lymphoma. Common genetic drivers for germinal center B cell-derived lymphomas have be identified through large scale sequencing efforts. However, transferring this knowledge into novel therapies remains challenging, particularly for loss-of-function mutations where the driver is absent and a valid therapeutic target is not immediately obvious. Up to 40% of germinal center-derived lymphomas, including both aggressive, diffuse large B-cell lymphoma (DLBCL), and indolent, follicular cell lymphoma (FL), contain loss of function mutations in histone acetyl transferases (HATs), CREBBP and p300, making loss-of-function mutations in HATs among the most common genetic alterations in lymphoma. Therapies aimed at these genetic alterations may therefore help large fraction of lymphoma patients. While loss of function mutations in HATs can be found at low frequency in other cancers, their extraordinarily high prevalence in DLBCL and FL suggests a fundamental role of dysregulated acetylation in the pathogenesis of germinal center-derived malignancies. Reduced activity of cellular HATs has been implicated in dysregulation of two critical mediators of lymphomagenesis, BCL6 and p53, which are rendered hyperactive and hypoactive, respectively, by the hypoacetylated state. We show that pharmacological inhibition SIRT2 counteracts the protein acetylation imbalance that drives lymphomagenesis, and thus constitutes a novel therapeutic strategy for treatment of germinal center-derived lymphomas. Our preliminary data validate this therapeutic strategy and provide evidence that BCL6 inactivation through SIRT2 inhibition consititues the basis for the anti-lymphoma activity. Based on this rationale and our preliminary data, we propose to: optimize SIRT2 inhibitors using medicinal chemistry and structure-based drug design; identify the mechanisms by which SIRT2 inhibitors abrogates BCL6 function, and; demonstrate in vivo anti-lymphoma activity. As a result, we will provide a novel therapeutic strategy and develop small molecule SIRT2 inhibitors, targeting one of the most common genetic alterations in germinal center-derived malignancies.

我们建议开发依赖NAD+的脱乙酰酶SIRT2抑制剂作为新的、靶向的、无毒的使BCL6失活的化疗药物，BCL6是B细胞淋巴瘤发生的关键驱动因素。普普通通生发中心B细胞性淋巴瘤的遗传驱动因素已通过大规模研究确定测序工作。然而，将这种知识转化为新的疗法仍然具有挑战性，尤其是对于驾驶员不在且有效治疗靶点不是立即有效的功能丧失突变很明显。高达40%的生发中心起源的淋巴瘤，包括侵袭性、弥漫性大B细胞淋巴瘤(DLBCL)和惰性滤泡细胞淋巴瘤(FL)包含组蛋白功能突变乙酰转移酶(HATS)，CREBBP和p300，使HATS功能丧失突变淋巴瘤中常见的基因改变。因此，针对这些基因改变的治疗可能会有所帮助很大一部分淋巴瘤患者。虽然在其他癌症中可以低频率地发现HATS功能突变的丧失，但它们的异常 DLBCL和FL的高患病率提示乙酰化失调在发病机制中的基础作用生发中心起源的恶性肿瘤。细胞内HAT活性降低与淋巴瘤发生的两个关键介质bcl6和p53的调节失调，这两个介质被认为是过度活跃的和低活性，分别通过低乙酰化状态。我们证明了药物抑制SIRT2 抵消了驱动淋巴肿大的蛋白质乙酰化失衡，从而构成了一种新的生发中心性淋巴瘤的治疗策略。我们的初步数据证实了这一点治疗策略及通过抑制SIRT2使BCL6失活的证据构成基础用于抗淋巴瘤的活动。基于这一理论基础和我们的初步数据，我们建议：优化SIRT2 使用药物化学和基于结构的药物设计的抑制剂；确定SIRT2的作用机制抑制剂取消了BCL6的功能，并在体内展示了抗淋巴瘤的活性。因此，我们将提供一种新的治疗策略并开发小分子SIRT2抑制剂，靶向最大的生发中心起源的恶性肿瘤中常见的基因改变。