Virtual ligand screening of the p300/CBP histone acetyltransferase: identification of a selective small molecule inhibitor.
Virtual ligand screening of the p300/CBP histone acetyltransferase: identification of a selective small molecule inhibitor.
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DOI：
10.1016/j.chembiol.2010.03.006
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发表时间：
2010-05-28
影响因子：
--
通讯作者：
Cole PA
中科院分区：
文献类型：
--
作者：
Bowers EM;Yan G;Mukherjee C;Orry A;Wang L;Holbert MA;Crump NT;Hazzalin CA;Liszczak G;Yuan H;Larocca C;Saldanha SA;Abagyan R;Sun Y;Meyers DJ;Marmorstein R;Mahadevan LC;Alani RM;Cole PA
组蛋白乙酰转移酶（HAT）p300/CBP是一种转录共激活因子，涉及许多基因调控途径和蛋白质乙酰化事件。虽然已有p300抑制剂的相关报道，但一种强效、选择性好且容易获得的作用于活性位点的小分子抑制剂尚未被发现。在此，我们采用一种基于结构的计算机虚拟筛选方法，鉴定出一种可商购的含吡唑啉酮的小分子p300 HAT抑制剂C646。C646是一种竞争性的p300抑制剂，其Ki值为400 nM，并且相对于其他乙酰转移酶具有选择性。对定点p300 HAT突变体的研究以及C646的合成修饰证实了预测的相互作用在赋予效力方面的重要性。C646在细胞中对组蛋白乙酰化和细胞生长的抑制作用验证了其作为一种药理探针的实用性，并表明p300/CBP HAT是一个有价值的抗癌靶点。
The histone acetyltransferase (HAT) p300/CBP is a transcriptional coactivator implicated in many gene regulatory pathways and protein acetylation events. While p300 inhibitors have been reported, a potent, selective, and readily available active-site directed small molecule inhibitor is not yet known. Here we use a structure-based, in silico screening approach to identify a commercially available pyrazolone-containing small molecule p300 HAT inhibitor, C646. C646 is a competitive p300 inhibitor with a Ki of 400 nM and is selective versus other acetyltransferases. Studies on site-directed p300 HAT mutants and synthetic modifications of C646 confirm the importance of predicted interactions in conferring potency. Inhibition of histone acetylation and cell growth by C646 in cells validate its utility as a pharmacologic probe and suggest that p300/CBP HAT is a worthy anti-cancer target.
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