Unknown

Dataset Information

0

Developing Spindlin1 small-molecule inhibitors by using protein microarrays.


ABSTRACT: 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.

SUBMITTER: Bae N 

PROVIDER: S-EPMC5831360 | BioStudies | 2017-01-01

REPOSITORIES: biostudies

Similar Datasets

2017-04-17 | GSE92547 | GEO
2012-01-01 | S-EPMC3497761 | BioStudies
2013-01-01 | S-EPMC3718791 | BioStudies
2011-01-01 | S-EPMC3207104 | BioStudies
1000-01-01 | S-EPMC4872087 | BioStudies
2014-01-01 | S-EPMC4161474 | BioStudies
2014-01-01 | S-EPMC3967050 | BioStudies
2018-11-29 | GSE123084 | GEO
2013-01-01 | S-EPMC3577944 | BioStudies
2013-01-01 | S-EPMC3830939 | BioStudies