Department of Chemistry, University of Minnesota, 207 Pleasant St. SE., Minneapolis, MN 55455, USA.
Org Biomol Chem. 2019 Feb 13;17(7):2020-2027. doi: 10.1039/c8ob02599a.
Bromodomain and PHD finger containing protein transcription factor (BPTF) is an epigenetic protein involved in chromatin remodelling and is a potential anticancer target. The BPTF bromodomain has one reported small molecule inhibitor (AU1, rac-1). Here, advances made on the structure-activity relationship of a BPTF bromodomain ligand are reported using a combination of experimental and molecular dynamics simulations leading to the active enatiomer (S)-1. Additionally, a ligand deconstruction analysis was conducted to characterize important pharmacophores for engaging the BPTF bromodomain. These studies have been enabled by a protein-based fluorine NMR approach, highlighting the versatility of the method for selectivity, ligand deconstruction, and ligand binding. To enable future analysis of biological activity, cell growth analyses in a panel of cancer cell lines were carried out using CRISPR-Cas9 and (S)-1 to identify cell-based model systems that are sensitive to BPTF inhibition.
溴结构域和 PH 结构域蛋白转录因子（BPTF）是一种参与染色质重塑的表观遗传蛋白，也是一种潜在的抗癌靶点。BPTF 的溴结构域有一个已报道的小分子抑制剂（AU1，rac-1）。本文报道了 BPTF 溴结构域配体的结构-活性关系的最新进展，采用了实验和分子动力学模拟相结合的方法，得到了活性对映异构体（S）-1。此外，还进行了配体解构分析，以确定与 BPTF 溴结构域结合的重要药效团。这些研究得益于基于蛋白质的氟 NMR 方法，该方法突出了该方法在选择性、配体解构和配体结合方面的多功能性。为了能够对生物活性进行进一步分析，使用 CRISPR-Cas9 和（S）-1 在一系列癌细胞系中进行了细胞生长分析，以确定对 BPTF 抑制敏感的基于细胞的模型系统。
