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

• 批准号: 8130537
• 负责人: Robert Michael Williams
• 金额: $ 30.57万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 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/8130537
• 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 Delivery Systems; 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; Screening procedure; 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; tool; vector

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. PUBLIC HEALTH RELEVANCE: The purpose of this application is to develop new classes of drugs that target a new and exciting biochemical target recently recognized as being essential to the cancer cell cycle. The new target is a class of enzymes that exist inside all cells called histone deacetylase enzymes (HDAC's). Our multidisciplinary project brings together synthetic organic chemistry, computational modeling, chemical biology and clinical evaluation of potential inhibitors of HDAC's.

描述(申请人提供)：本申请的主要重点是开发更有效和毒性更低的、同种形式选择性的组蛋白脱乙酰酶(HDACi)抑制剂(HDACi)，用作抗骨髓瘤和抗癌候选药物，用于研究单个HDAC的特定功能的生物工具，并将这一化学类别扩展到抗肿瘤适应症之外。具体地说，我们计划通过根据目标酶的晶体结构得出的参数改变氨基酸序列和锌结合功能来优化大环肽类似物的结构，并利用额外的计算和经验见解来优化大环肽类似物和相关的天然HDAC抑制剂的HDAC类选择性。类似物将在哈佛-麻省理工学院博德研究所的詹姆斯·E·布拉德纳博士和达纳-法伯癌症研究所的合作者詹姆斯·E·布拉德纳博士以及骨髓瘤和骨癌研究所的詹姆斯·R·贝伦森博士的实验室中进行对HDAC 1-11的抑制活性测试。安全性和药效学效果的评估将由道格拉斯·萨姆教授和CSU兽医和生物医学学院的同事进行。从这些分析结果中获得的洞察力将指导候选结构的进一步改变。圣母大学的计算机合作者Olaf Wiest教授将开展基于同源模型的对接研究，以进一步指导新的合成HDACi的设计和优化。我们已经开发了已知的、高度有效的天然HDACi的精胺和FK228以及相应的多肽同工酶和这些有效的和自然产生的HDACi的大量合成类似物的可扩展的溶液相合成。通过改变三个参数来探索类似物的结构多样性：(A)氨基酸序列和组成；(B)大环大小；(C)锌结合臂。通过这种方法产生的特别有效的和/或具有异构体选择性的大环肽抑制剂将作为相应的脱脂多肽同系物重新合成，并在生化和细胞分析中进行效价和特异性分析。我们将评估特定异构体类似物在体内的耐受性和抗肿瘤活性。 公共卫生相关性：这项申请的目的是开发新的药物类别，目标是最近被认为对癌细胞周期至关重要的一种新的、令人兴奋的生化靶点。新的目标是一类存在于所有细胞中的酶，称为组蛋白脱乙酰酶(HDAC)。我们的多学科项目结合了合成有机化学、计算建模、化学生物学和HDAC潜在抑制剂的临床评估。