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Histone Deacetylase Inhibitors for Cancer Treatment

用于癌症治疗的组蛋白脱乙酰酶抑制剂

基本信息

批准号：
6988925
负责人：
GERALD A SOFF
金额：
$ 13.59万
依托单位：
ANGIOGEN, INC.
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-08-12 至 2006-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6988925
关键词：
amidohydrolases antineoplastics breast neoplasms cell line cell proliferation drug design /synthesis /production drug screening /evaluation enzyme activity enzyme inhibitors melanoma metalloenzyme neoplasm /cancer chemotherapy pancreas neoplasms peptide analog peptide chemical synthesis prostate neoplasms zinc

项目摘要

DESCRIPTION (provided by applicant): Histone deacetylases (HDACs) comprise a family of enzymes that catalyze the removal of acetyl groups from lysine residues of histones. They mediate chromatin remodeling and gene expression. HDAC inhibitors are potent inducers of growth arrest, differentiation or apoptic cell death and suppress cell proliferation in a variety of transformed cells in culture and in tumor bearing animals. Several HDAC inhibitors are in clinical trials as anticancer agents. Class I/I I histone deacetylases are metalloenzymes with a zinc ion at the active site. A crystal structure of a hydroxamate inhibitor bound to histone deacetylase showed that hydroxamates coordinate to the zinc ion. Hydroxamic acid appears to be the zinc ligand that almost all investigators use, even in 2004. However, hydroxamic acid derivatives often present metabolic and pharmacokinetic problems such as glucoronidation, sulfation and enzymatic hydrolysis that result in short in-vivo half lives. Nonhydroxamate HDAC inhibitors discovered so far have reduced potency compared to hydroxamates. There are currently 11 reported human class l/ll HDAC isoforms. A concerted effort has not been made for the development of HDAC isoform-selective inhibitors. Specific inhibition of HDAC isoforms for cancer may offer opportunities for improved specificity and reduced toxicity. Natural cyclic tetrapeptides are well known histone deacetylase inhibitors. Based on an inspection of SARs of known histone deacetylase inhibitors, an ideal HDAC inhibitor should be composed of an improved zinc binding ligand coupled through a spacer to the cyclic tetrapeptide core structure. Specific Aims: (1) The solid-phase synthesis of hydrophobic cyclic tetrapeptides as inhibitors of Zn(ll)-dependent histone deacetylases will be carried out. (2) Novel zinc ligands for the inhibition of histone deacetylase will be incorporated into the backbone of potent cyclic tetrapeptide analogues for further enhancement of activity. (3) These compounds will be assayed for histone deacetylase activity and for antitumor activity in a variety of cancer cells.

描述（由申请人提供）：组蛋白脱乙酰酶（HDAC）包含催化从组蛋白的赖氨酸残基中去除乙酰基的酶家族。它们介导染色质重塑和基因表达。 HDAC 抑制剂是生长停滞、分化或凋亡细胞死亡的有效诱导剂，并抑制培养物和荷瘤动物中各种转化细胞的细胞增殖。几种 HDAC 抑制剂作为抗癌药物正在进行临床试验。 I/I I 类组蛋白脱乙酰酶是活性位点带有锌离子的金属酶。与组蛋白脱乙酰酶结合的异羟肟酸抑制剂的晶体结构表明异羟肟酸与锌离子配位。即使在 2004 年，异羟肟酸似乎是几乎所有研究人员都使用的锌配体。然而，异羟肟酸衍生物经常出现代谢和药代动力学问题，例如葡萄糖醛酸化、硫酸化和酶水解，导致体内半衰期短。迄今为止发现的非异羟肟酸盐 HDAC 抑制剂与异羟肟酸盐相比，其效力较低。目前已报道了 11 种人类 l/ll 类 HDAC 亚型。目前尚未共同努力开发 HDAC 异构体选择性抑制剂。对癌症 HDAC 亚型的特异性抑制可能为提高特异性和降低毒性提供机会。天然环状四肽是众所周知的组蛋白脱乙酰酶抑制剂。根据对已知组蛋白脱乙酰酶抑制剂的 SAR 的检查，理想的 HDAC 抑制剂应由通过间隔基偶联至环状四肽核心结构的改进的锌结合配体组成。具体目标： (1) 固相合成疏水性环状四肽作为Zn(II)依赖性组蛋白脱乙酰酶抑制剂。 (2)用于抑制组蛋白脱乙酰酶的新型锌配体将被纳入有效的环状四肽类似物的主链中，以进一步增强活性。 (3) 将测定这些化合物的组蛋白脱乙酰酶活性和多种癌细胞中的抗肿瘤活性。