Institute of Pharmaceutical Sciences, Albert-Ludwigs-University of Freiburg, Germany.
Bioorg Med Chem. 2011 Jun 15;19(12):3678-89. doi: 10.1016/j.bmc.2011.01.063. Epub 2011 Feb 2.
We present a combination of database screening, synthesis and in vitro testing to identify novel histone acetyltransferase (HAT) inhibitors. The National Cancer Institute compound collection (NCI) and several commercial databases were filtered by similarity-based virtual screening to find new HAT inhibitors. Employing the recombinant HAT p300/CBP-associated factor (PCAF) and two different histone substrates for screening, pyridoisothiazolones were identified as inhibitors of human PCAF. Due to the limited solubility of the initial hits, we synthesized and tested them on PCAF. The compounds inhibit the proliferation of cancer cells. In summary, valuable chemical tools and potential lead candidates for new anticancer agents directed against HATs as new targets have been identified.
我们提出了一种结合数据库筛选、合成和体外测试的方法，用于鉴定新型组蛋白乙酰转移酶（HAT）抑制剂。通过基于相似性的虚拟筛选，对国家癌症研究所化合物库（NCI）和几个商业数据库进行了过滤，以寻找新的 HAT 抑制剂。使用重组 HAT p300/CBP 相关因子（PCAF）和两种不同的组蛋白底物进行筛选，发现吡啶并异噻唑酮类化合物是人类 PCAF 的抑制剂。由于最初的命中物的溶解度有限，我们对其进行了合成并在 PCAF 上进行了测试。这些化合物抑制癌细胞的增殖。总之，已经鉴定出针对 HAT 作为新靶标的新型抗癌剂的有价值的化学工具和潜在的先导候选物。
