Multiple Myeloma and Cancer Therapies via Largazole Analogs

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。

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.