发现具有良好体外和体内抗肿瘤活性的新型I类组蛋白去乙酰化酶抑制剂。
Discovery of Novel Class I Histone Deacetylase Inhibitors with Promising in Vitro and in Vivo Antitumor Activities.
作者信息
Yao Yiwu, Tu Zhengchao, Liao Chenzhong, Wang Zhen, Li Shang, Yao Hequan, Li Zheng, Jiang Sheng
机构信息
Laboratory of Medicinal Chemistry, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
School of Medical Engineering, Hefei University of Technology , Hefei, Anhui 230009, China.
出版信息
J Med Chem. 2015 Oct 8;58(19):7672-80. doi: 10.1021/acs.jmedchem.5b01044. Epub 2015 Sep 16.
A successful structure-based design of novel cyclic depsipeptides that selectively target class I HDAC isoforms is described. Compound 11 has an IC50 of 2.78 nM for binding to the HDAC1 protein, and the prodrugs 12 and 13 also exhibit promising antiproliferative activities in the nanomolar range against various cancer cell lines. Compounds 12 and 13 show more than 20-fold selectivity toward human cancer cells over human normal cells in comparison with romidepsin (FK228), demonstrating low probability of toxic side effects. In addition, compound 13 exhibits excellent in vivo anticancer activities in a human prostate carcinoma (Du145) xenograft model with no observed toxicity. Thus, prodrug 13 has therapeutic potential as a new class of anticancer agent for further clinical translation.
本文描述了一种成功的基于结构的新型环缩肽设计，该环缩肽可选择性靶向I类组蛋白去乙酰化酶（HDAC）亚型。化合物11与HDAC1蛋白结合的IC50为2.78 nM，前药12和13在纳摩尔范围内对多种癌细胞系也表现出有前景的抗增殖活性。与罗米地辛（FK228）相比，化合物12和13对人癌细胞的选择性比对人正常细胞高20多倍，表明其产生毒副作用的可能性较低。此外，化合物13在人前列腺癌（Du145）异种移植模型中表现出优异的体内抗癌活性，且未观察到毒性。因此，前药13作为一类新型抗癌剂具有进一步临床转化的治疗潜力。
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