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: 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
• 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

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开发更有效、毒性更低的异构体选择性组蛋白脱乙酰酶 (HDAC) 抑制剂 (HDACi)，用作抗骨髓瘤和抗癌候选药物、用于研究个体 HDAC 特定功能的生物工具以及将此类化学类别扩展到抗肿瘤适应症之外。具体来说，我们计划通过根据目标酶晶体结构衍生的参数改变氨基酸序列和锌结合功能，利用额外的计算和经验见解，优化拉格唑大环肽类似物和相关天然存在的 HDAC 抑制剂的结构，以实现 HDAC 类别选择性。类似物对 HDAC 1-11 的抑制活性将在哈佛-麻省理工学院博德研究所和达纳法伯癌症研究所的联合研究员 James E. Bradner 博士以及骨髓瘤和骨癌研究所的 James R. Berenson 博士的实验室进行检测。安全性和药效学效果的评估将由科罗拉多州立大学兽医和生物医学学院的 Douglas Thamm 教授及其同事进行。从这些测定结果中获得的见解将指导候选结构的进一步改变。圣母大学的计算联合研究员 Olaf Wiest 教授将部署基于同源模型的对接研究，以进一步指导新型合成 HDACi 的设计和优化。我们开发了已知的高效天然 HDACi 的拉格唑和 FK228 以及相应的肽电子等排物和这些有效的天然 HDACi 的许多合成类似物的可规模化溶液相合成方法。将通过改变三个参数来探索类似物内的结构多样性：（a）氨基酸序列和构成； (b) 大环尺寸； (c) 锌结合臂。通过这种方法产生的特别有效的和/或异构体选择性的大环肽抑制剂将被靶向重新合成为相应的缩酚肽同系物，并在生化和细胞测定中分析效力和特异性。将评估选择的异构体特异性类似物的体内耐受性和抗肿瘤活性。