期刊
NATURE CHEMICAL BIOLOGY
卷 13, 期 7, 页码 750-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nchembio.2377
关键词
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资金
- NIH [DK062248]
- CPRIT grant [RP130432, RP120348]
- Center for Cancer Epigenetics at MDACC
- Italian Ministero dell'Istruzione, dell'Universita e della Ricerca (MIUR), Progetti di Ricerca di Interesse Nazionale (PRIN) [2012ZHN9YH]
- Universita di Salerno (Italy)
- European Cooperation in Science and Technology (COST Action) [CM1406]
- Major State Basic Research Development Program in China [2015CB910503, 2016YFA0500700]
- Tsinghua University Initiative Scientific Research Program
- Odyssey Fellowship Program at the University of Texas MD Anderson Cancer Center
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.
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