Discovery of a Tetrahydroisoquinoline-Based Hydroxamic Acid Derivative (ZYJ-34c) as Histone Deacetylase Inhibitor with Potent Oral Antitumor Activities
Discovery of a Tetrahydroisoquinoline-Based Hydroxamic Acid Derivative (ZYJ-34c) as Histone Deacetylase Inhibitor with Potent Oral Antitumor Activities
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发现四氢异喹啉基异羟肟酸衍生物 (ZYJ-34c) 作为组蛋白脱乙酰酶抑制剂，具有有效的口服抗肿瘤活性
DOI：
10.1021/jm200577a
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发表时间：
2011-08-11
影响因子：
7.3
通讯作者：
Xu, Wenfang
中科院分区：
文献类型：
--
作者：
Zhang, Yingjie;Fang, Hao;Xu, Wenfang
在过去的十年中，组蛋白脱乙酰酶（HDAC）已成为抗肿瘤药物开发的一个有吸引力的靶点。此前，含四氢异喹啉的异羟肟酸类似物 ZYJ-25e (1) 被鉴定并验证为有效的组蛋白脱乙酰酶抑制剂 (HDACi)，具有显着的体外和体内抗肿瘤效力。在本研究中，1 的进一步修饰产生了另一种更有效的口服活性 HDACi，ZYJ-34c (4)。与FDA批准的药物辛二酰苯胺异羟肟酸（SAHA）相比，化合物4在人乳腺癌（MDA-MB-231）异种移植模型和小鼠hepatoma-22（H22）肺转移模型中表现出更高的体内抗肿瘤效力，在人结肠肿瘤（HCT116）异种移植模型中表现出相似的体内抗肿瘤效力。
Histone deacetylase (HDAC) has emerged as an attractive target for the development of antitumor agents during the past decade. Previously tetrahydroisoquinoline-bearing hydroxamic acid analogue, ZYJ-25e (1), was identified and validated as a potent histone deacetylase inhibitor (HDACi) with marked in vitro and in vivo antitumor potency. In the present study, further modification of 1 led to another more potent, orally active HDACi, ZYJ-34c (4). Compared to FDA-approved drug suberoylanilide hydroxamic acid (SAHA), compound 4 exhibited higher in vivo antitumor potency in a human breast carcinoma (MDA-MB-231) xenograft model and in a mouse hepatoma-22 (H22) pulmonary metastasis model and similar in vivo antitumor potency in a human colon tumor (HCT116) xenograft model.