Pathway-Based High-Throughput Chemical Screen Identifies Compounds That Decouple Heterochromatin Transformations.

ABSTRACT: Heterochromatin protein 1 (HP1) facilitates the formation of repressive heterochromatin domains by recruiting histone lysine methyltransferase enzymes to chromatin, resulting in increased levels of histone H3K9me3. To identify chemical inhibitors of the HP1-heterochromatin gene repression pathway, we combined a cell-based assay that utilized chemical-mediated recruitment of HP1 to an endogenous active gene with high-throughput flow cytometry. Here we characterized small molecule inhibitors that block HP1-mediated heterochromatin formation. Our lead compounds demonstrated dose-dependent inhibition of HP1-stimulated gene repression and were validated in an orthogonal cell-based system. One lead inhibitor was improved by a change in stereochemistry, resulting in compound 2, which was further

SUBMITTER: MacDonald IA 

PROVIDER: S-EPMC6893849 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature