Multiple Myeloma and Cancer Therapies via Largazole Analogs

通过拉格唑类似物治疗多发性骨髓瘤和癌症

基本信息

批准号：
8510596
负责人：
Robert Michael Williams
金额：
$ 28.77万
依托单位：
COLORADO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8510596
关键词：
Amino Acid Sequence Antineoplastic Agents Binding Biochemical Biological Biological Assay Biological Factors Biology Cancer cell line Cell Cycle Cells Cellular Assay Chemicals Clinical Collection Computer Assisted Computer Simulation Constitution Crystallization Dana-Farber Cancer Institute Depsipeptides Development Disease Docking Dose-Limiting Drug Targeting Enzymes Epigenetic Process Exhibits Gene Expression Profiling Hematologic Neoplasms Histone Deacetylase Histone Deacetylase Inhibitor Homology Modeling Human In Vitro Individual Institutes Investigation Laboratories Lead Link Malignant Bone Neoplasm Modeling Molecular Multiple Myeloma National Cancer Institute Organic Chemistry Patients Peptides Pharmacodynamics Property Protein Isoforms RNA Interference Recombinants Research Research Personnel S Phase Safety Science Solutions Specificity Structure Therapeutic Therapeutic Agents Toxic effect Universities Veterinary Medicine Zinc analog anticancer research arm base cancer cell cancer therapy chemical genetics college comparative design drug candidate in vivo in vivo Model inhibitor/antagonist insight milligram multidisciplinary neoplastic novel peptide analog preclinical study programs public health relevance research clinical testing research study scaffold screening tool vector

项目摘要

DESCRIPTION (provided by applicant): The primary focus of this application is to develop more potent and less toxic, isoform-selective histone deacetylase (HDAC) inhibitors (HDACi) for use as anti-myeloma and anti-cancer drug candidates, biological tools for investigation of specific functions of individual HDACs and extension of this chemical class beyond antineoplastic indications. Specifically, we plan to optimize the structures of macrocyclic peptide analogues of largazole, and related naturally occurring HDAC inhibitors for HDAC class- selectivity by altering the amino acid sequence and zinc-binding functionality in accord with parameters derived from crystal structures of the target enzymes deploying additional computational and empiric insights. Analogues will be assayed for inhibitory activity against HDACs 1-11 in the laboratories of co- investigator Dr. James E. Bradner at the Broad Institute of Harvard-MIT and the Dana-Farber Cancer Institute and Dr. James R. Berenson at the Institute for Myeloma and Bone Cancer Research. Assessment of the safety and pharmacodynamic effect will be performed by Prof. Douglas Thamm and co- workers at the CSU College of Veterinary Medicine and Biomedical Sciences. Insight from the results of these assays will guide further alterations of the candidate structures. A computational co-investigator, Prof. Olaf Wiest, at the University of Notre Dame, will deploy homology model-based docking studies to further guide the design and optimization of new synthetic HDACi's. We have developed scaleable solution-phase syntheses of the known, highly potent natural HDACi's largazole and FK228 as well as the corresponding peptide isosteres and numerous synthetic analogs of these potent and naturally occurring HDACi's. Structural diversity within the analogs will be explored by varying three parameters: (a) amino acid sequence and constitution; (b) macrocycle size; and (c) zinc-binding arms. Particularly potent and/or isoform-selective macrocyclic peptide inhibitors that are produced by this approach will be targeted for re-synthesis as the corresponding depsipeptide congeners and profiled for potency and specificity in biochemical and cellular assays. Select isoform-specific analogs will be evaluated for in vivo tolerability and antineoplastic activity.

描述（由申请人提供）：本申请的主要重点是发展更有效，毒性，同工选择性组蛋白脱乙酰基酶（HDAC）抑制剂（HDACI），用作抗肿瘤瘤和抗癌药物候选物，生物学工具，用于研究该化学分类的特定功能以及Antine Antine的生物功能。具体而言，我们计划通过改变来自来自靶标enzymes的晶体结构的参数，通过更改氨基酸序列和锌结合功能来优化大量大量的大环类似物的结构，并通过改变靶enzymes的晶体结构来实现其他计算和Empiric Inspirics inspirics Inspirics的晶体结构来优化HDAC类选择性的自然存在的HDAC抑制剂。将在哈佛大学广泛研究所的合伙人James E. Bradner博士和Dana-Farber Cancer Institute和Dana-Farber Cancer Institute和Dana-Farber Cancer Institute和Dana R. Berenson博士的骨髓瘤和骨癌研究所的James R. Berenson博士的同事詹姆斯·E·布拉德纳（James E. CSU兽医学院和生物医学科学学院的道格拉斯·塞姆（Douglas Thamm）教授和同事将对安全和药效效应进行评估。这些测定结果的洞察力将指导候选结构的进一步改变。巴黎圣母院大学的计算共同研究员奥拉夫·威斯特（Olaf Wiest）教授将部署基于同源性模型的扩展坞研究，以进一步指导新的合成HDACI的设计和优化。我们已经开发了可扩展的溶液相合成的合成，这些合成具有高度有效的天然HDACI的Largazole和FK228，以及相应的肽等当剂以及这些有效且自然存在的HDACI的众多合成类似物。通过改变三个参数，将探索类似物中的结构多样性：（a）氨基酸序列和构造；（b）大环的大小；（c）锌结合臂。该方法产生的特别有效和/或同工型选择性的大环肽抑制剂将被靶向重新合成为相应的二肽同类物，并在生物化学和细胞测定中介绍了效力和特异性。将评估选择的同工型特异性类似物的体内耐受性和抗塑性活性。