Rational design and validation of a Tip60 histone acetyltransferase inhibitor.
Rational design and validation of a Tip60 histone acetyltransferase inhibitor.
复制标题
DOI：
10.1038/srep05372
复制
发表时间：
2014-06-20
影响因子：
4.6
通讯作者：
Brown JA
中科院分区：
文献类型：
--
作者：
Gao C;Bourke E;Scobie M;Famme MA;Koolmeister T;Helleday T;Eriksson LA;Lowndes NF;Brown JA
组蛋白乙酰化是基因调控、基因组维持和代谢的许多方面所必需的，并且功能障碍性乙酰化涉及许多疾病，包括癌症。乙酰化是由组蛋白乙酰转移酶（HAT）和组蛋白脱乙酰酶调节的，目前，很少有通用的HAT抑制剂被描述。我们将HAT Tip60确定为靶向药物开发的优秀候选者，因为Tip60是DNA损伤反应和转录共激活因子的关键介体。我们对Tip60的建模表明，活性结合口袋在两端具有相反的电荷，正电荷归因于两个特定的侧链。我们使用基于结构的药物设计开发了一种新型Tip60抑制剂TH1834，以适应这种特定的口袋。我们证明，TH1834显着抑制Tip60活性在体外和治疗细胞与TH1834的结果在乳腺癌细胞凋亡和未修复的DNA损伤（电离辐射治疗后），但不控制细胞系。此外，TH1834不影响相关HAT MOF的活性，如H4K16Ac所示，证明了特异性。小分子抑制剂TH1834的建模和验证代表了开发其他特异性靶向Tip60抑制剂的第一步，这可能导致乳腺癌治疗的进一步改善。
Histone acetylation is required for many aspects of gene regulation, genome maintenance and metabolism and dysfunctional acetylation is implicated in numerous diseases, including cancer. Acetylation is regulated by histone acetyltransferases (HATs) and histone deacetylases and currently, few general HAT inhibitors have been described. We identified the HAT Tip60 as an excellent candidate for targeted drug development, as Tip60 is a key mediator of the DNA damage response and transcriptional co-activator. Our modeling of Tip60 indicated that the active binding pocket possesses opposite charges at each end, with the positive charges attributed to two specific side chains. We used structure based drug design to develop a novel Tip60 inhibitor, TH1834, to fit this specific pocket. We demonstrate that TH1834 significantly inhibits Tip60 activity in vitro and treating cells with TH1834 results in apoptosis and increased unrepaired DNA damage (following ionizing radiation treatment) in breast cancer but not control cell lines. Furthermore, TH1834 did not affect the activity of related HAT MOF, as indicated by H4K16Ac, demonstrating specificity. The modeling and validation of the small molecule inhibitor TH1834 represents a first step towards developing additional specific, targeted inhibitors of Tip60 that may lead to further improvements in the treatment of breast cancer.
登录
查看更多内容
影响因子：
5.3
作者：
Jha, Sudhakar;Shibata, Etsuko;Dutta, Anindya
通讯作者：
Dutta, Anindya
影响因子：
3.9
作者：
Gozdecka, Malgorzata;Breitwieser, Wolfgang
通讯作者：
Breitwieser, Wolfgang
影响因子：
3
作者：
Duan, Y;Wu, C;Kollman, P
通讯作者：
Kollman, P
影响因子：
4.2
作者：
Bonkhoff H
通讯作者：
Bonkhoff H
影响因子：
2.9
作者：
Krieger, E;Darden, T;Vriend, G
通讯作者：
Vriend, G