Nonpeptide macrocyclic histone deacetylase (HDAC) inhibitors for targeted lung ca

用于靶向肺癌的非肽大环组蛋白脱乙酰酶 (HDAC) 抑制剂

基本信息

批准号：
7785028
负责人：
Adegboyega Oyelere
金额：
$ 29.55万
依托单位：
GEORGIA INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-25 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7785028
关键词：
A549 Adverse effects Antineoplastic Agents Azithromycin Behavior Binding Biochemical Biological Assay Cancer Etiology Cancer Model Cancer cell line Cell Line Cells Cervix Uteri Cessation of life Chromatin Collection Cutaneous Cyclic Peptides DNA Data Deacetylase Deacetylation Docking Drug Kinetics Drug or chemical Tissue Distribution Enzymatic Biochemistry Enzymes Epithelial Cells Excision FDA approved Family Fibroblasts Genes Goals Gonadotropin-Releasing Hormone Receptor HDAC7 histone deacetylase Health Histone Deacetylase Histone Deacetylase Inhibitor Histone deacetylase inhibition Histones Human In Vitro Lead Literature Lung Lysine Macrolide Antibiotics Macrolides Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of prostate Mammary gland Methods Molecular Mus Organ Organic Chemistry Patients Pattern Peptides Protein Acetylation Protein Isoforms Reaction Research Research Design Role Series Side Skeleton Structure Survival Rate T-Cell Lymphoma Therapeutic Therapeutic Index Tissues Tonsil Vertebral column Vorinostat Xenograft Model base cancer therapy cell transformation cell type chemotherapeutic agent computational chemistry design gene repression hydroxamate improved in vivo inhibitor/antagonist insight lung small cell carcinoma male novel novel therapeutics outcome forecast pharmacophore pre-clinical public health relevance research clinical testing research study spelling tool tumor

项目摘要

DESCRIPTION (provided by applicant): We seek to identify novel nonpeptide macrocyclic histone deacetylase (HDAC) inhibitors as a new class of anticancer agents. HDAC inhibitors hold great promise in cancer therapy due to their demonstrated ability to arrest proliferation of nearly all transformed cell types. However, most of these agents are non-selective inhibitors of all HDAC isoforms; and a large number of the identified HDAC inhibitors have not progressed beyond preclinical characterizations. Our hypothesis in this proposal is that substitution of the peptide moiety of a prototypical cyclic- peptide HDAC inhibitor with specific non-peptidyl macrocyclic surrogates will generate a new class of potent HDAC inhibitors with improved therapeutic index. These compounds are anticipated to also possess targeted anti-cancer activity due to selective tissue distribution conferred by the appended macrocyclic moiety. In Preliminary Results a class of macrocyclic hydroxamates has been identified. The goal of this application is to study the molecular mechanisms underlying the in vitro anti-HDAC and anti-tumor activities of these compounds. Aim 1 is to develop novel nonpeptide macrocyclic HDAC inhibitors. The first step here is to broaden our design approach to include other structurally similar macrocyclic templates in order to create a tool set upon which subsequent structure activity relation (SAR) studies will be based. To guide this effort, we will use molecular docking (AutoDock) to investigate the SAR of the combination of these macrocyclic templates with key HDAC inhibitor pharmacophores. Aim 2 is to characterize the structural and biochemical requirements for in vitro and whole cell HDAC inhibition. Toward this end, we will profile the anti-HDAC activity of compounds obtained from the priority list generated by the docking experiments using both in vitro HDAC inhibition assay and whole cell activity in human lung cancer cell lines. Moreover, we will evaluate the whole cell mechanism of our potent inhibitors based on intracellular status of p21WAF1/CIP1 and HDAC7 genes, and histone protein acetylation patterns. Our Aim 3 is to investigate the organ distribution and in vivo efficacy of lead compounds in mice. We will first study compound organ distribution behavior in healthy male Balb/c mice. Compounds displaying lung selective accumulation with good pharmacokinetic parameters will then be advanced to in vivo efficacy studies in Balb/c (nu/nu) mice bearing xenograft models of specific lung cancers. In the longer term, we will identify series of novel HDAC inhibitors that will be advanced to further preclinical/clinical evaluations. Additionally, the proposed studies will yield new insights on the roles of HDACs in the etiology of cancer. PUBLIC HEALTH RELEVANCE: Lung cancer is the leading cause of cancer deaths in the US. Outlined in this proposal is a method that will enable identification of new classes of chemotherapeutic agents that possess lung- selective anti-cancer activity for targeted lung cancer therapy applications. Our proposed approach is expected to lead to chemotherapeutic agents with superior therapeutic indices and will significantly impact patient survival prognosis and positively contribute to human health management.

描述（由申请人提供）：我们试图将新型的非肽大环组蛋白脱乙酰基酶（HDAC）抑制剂作为新类别的抗癌药。 HDAC抑制剂在癌症治疗方面具有巨大的前景，因为它们表现出了几乎所有转化的细胞类型的增殖的能力。但是，这些药物中的大多数是所有HDAC同工型的非选择性抑制剂。而且，大量已鉴定的HDAC抑制剂尚未超出临床前表征。我们在该提案中的假设是，用特定的非肽基大环替代物取代了原型环肽HDAC抑制剂的肽部分，将产生一类新的有效HDAC抑制剂，并具有改善的治疗指数。预计这些化合物还具有靶向的抗癌活性，这是由于插入的大环部分所赋予的选择性组织分布。在初步结果中，已经鉴定出一类宏观羟氨氨基盐。该应用的目的是研究这些化合物的体外抗HDAC和抗肿瘤活性的分子机制。目的1是开发新型的非肽大环HDAC抑制剂。这里的第一步是扩大我们的设计方法，以包括其他结构相似的大环模板，以创建一个工具集，然后将其随后的结构活动关系（SAR）研究基于该工具。为了指导这项工作，我们将使用分子对接（Autodock）来研究这些大环模板与关键HDAC抑制剂药理的组合。目的2是表征体外和全细胞HDAC抑制的结构和生化需求。为此，我们将介绍从对接实验产生的优先级列表中使用体外HDAC抑制测定和整个细胞活性在人类肺癌细胞系中产生的抗HDAC活性。此外，我们将根据P21WAF1/CIP1和HDAC7基因的细胞内状态以及组蛋白蛋白乙酰化模式来评估有效抑制剂的整个细胞机制。我们的目标3是研究小鼠铅化合物的器官分布和体内功效。我们将首先研究健康男性BALB/C小鼠的复合器官分布行为。然后将具有良好药代动力学参数的肺选择性积累的化合物推进到BALB/C（NU/NU）小鼠中具有特定肺癌的异种移植模型的体内功效研究。从长远来看，我们将确定一系列新型的HDAC抑制剂，这些抑制剂将用于进一步的临床前/临床评估。此外，拟议的研究将对HDAC在癌症病因中的作用产生新的见解。公共卫生相关性：肺癌是美国癌症死亡的主要原因。该提案中概述的是一种方法，它将能够鉴定具有针对靶向肺癌治疗应用的肺选择性抗癌活性的新型化学治疗剂。我们提出的方法有望导致具有优质治疗指数的化学治疗剂，并将显着影响患者的生存预后，并对人类健康管理产生积极的贡献。