Developing Spindlin1 small-molecule inhibitors by using protein microarrays

作者：Bae, Narkhyun; Viviano, Monica; Su, Xiaonan; Lv, Jie; Cheng, Donghang; Sagum, Cari; Castellano, Sabrina; Bai, Xue; Johnson, Claire; Khalil, Mahmoud Ibrahim; Shen, Jianjun; Chen, Kaifu; Li, Haitao^*; Sbardella, Gianluca^*; Bedford, Mark T.^*

来源：Nature Chemical Biology, 2017, 13(7): 750-+.

DOI：10.1038/nchembio.2377

• CHEMICAL PROBE
• HISTONE
• IDENTIFICATION
• BINDING
• DISCOVERY
• METHYLATION
• ANTAGONISTS
• TARGET
• LIGAND
• POCKET

The discovery of inhibitors of methyl-and acetyl-binding domains has provided evidence for the 'druggability' of epigenetic effector molecules. The small-molecule probe UNC1215 prevents methyl-dependent protein-protein interactions by engaging the aromatic cage of MBT domains and, with lower affinity, Tudor domains. Using a library of tagged UNC1215 analogs, we screened a protein-domain microarray of human methyllysine effector molecules to rapidly detect compounds with new binding profiles with either increased or decreased specificity. Using this approach, we identified a compound (EML405) that acquired a novel interaction with the Tudor-domain-containing protein Spindlin1 (SPIN1). Structural studies facilitated the rational synthesis of SPIN1 inhibitors with increased selectivity (EML631-633), which engage SPIN1 in cells, block its ability to 'read' H3K4me3 marks and inhibit its transcriptional-coactivator activity. Protein microarrays can thus be used as a platform to 'target-hop' and identify small molecules that bind and compete with domain-motif interactions.

• 出版日期2017-7
• 单位清华大学