Histone Deacetylase Inhibitors for Cancer Treatment

描述（由申请人提供）：组蛋白去乙酰化酶（hdac）包括催化从组蛋白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，并抑制培养和荷瘤动物中多种转化细胞的细胞增殖。几种HDAC抑制剂作为抗癌药物正在临床试验中。I/I类组蛋白去乙酰化酶是活性位点有锌离子的金属酶。与组蛋白去乙酰化酶结合的羟酸盐抑制剂的晶体结构表明，羟酸盐与锌离子配位。羟肟酸似乎是锌的配体，几乎所有的研究人员使用，甚至在2004年。然而，羟肟酸衍生物通常存在代谢和药代动力学问题，如糖醛酸化、硫酸酸化和酶解，导致体内半衰期短。迄今为止发现的非羟酸类HDAC抑制剂与羟酸类相比效力较低。目前已报道的人类ⅰ/ⅱ类HDAC亚型有11种。对于HDAC异构体选择性抑制剂的开发还没有达成一致的努力。对癌症的HDAC异构体的特异性抑制可能为提高特异性和降低毒性提供机会。天然环四肽是众所周知的组蛋白去乙酰化酶抑制剂。根据对已知组蛋白去乙酰化酶抑制剂的SARs的检查，理想的HDAC抑制剂应该由改进的锌结合配体通过间隔剂偶联到环四肽核心结构组成。具体目的：(1)固相合成作为Zn（ll）依赖性组蛋白去乙酰化酶抑制剂的疏水环四肽。(2)抑制组蛋白去乙酰化酶的新型锌配体将被纳入强效环四肽类似物的主链中，以进一步增强活性。(3)这些化合物将在多种癌细胞中检测组蛋白去乙酰化酶活性和抗肿瘤活性。

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.