Design and Construction of a Focused DNA-Encoded Library for Multivalent Chromatin Reader Proteins
Open Access
- 22 February 2020
- Vol. 25 (4), 979
- https://doi.org/10.3390/molecules25040979
Abstract
Chromatin structure and function, and consequently cellular phenotype, is regulated in part by a network of chromatin-modifying enzymes that place post-translational modifications (PTMs) on histone tails. These marks serve as recruitment sites for other chromatin regulatory complexes that ‘read’ these PTMs. High-quality chemical probes that can block reader functions of proteins involved in chromatin regulation are important tools to improve our understanding of pathways involved in chromatin dynamics. Insight into the intricate system of chromatin PTMs and their context within the epigenome is also therapeutically important as misregulation of this complex system is implicated in numerous human diseases. Using computational methods, along with structure-based knowledge, we have designed and constructed a focused DNA-Encoded Library (DEL) containing approximately 60,000 compounds targeting bi-valent methyl-lysine (Kme) reader domains. Additionally, we have constructed DNA-barcoded control compounds to allow optimization of selection conditions using a model Kme reader domain. We anticipate that this target-class focused approach will serve as a new method for rapid discovery of inhibitors for multivalent chromatin reader domains.Funding Information
- National Institutes of Health (NIH 5R01 GM100919-06)
This publication has 80 references indexed in Scilit:
- A Poised Chromatin Platform for TGF-β Access to Master RegulatorsCell, 2011
- Prognostic Significance of TRIM24/TIF-1α Gene Expression in Breast CancerThe American Journal of Pathology, 2011
- Transcription cofactors TRIM24, TRIM28, and TRIM33 associate to form regulatory complexes that suppress murine hepatocellular carcinomaProceedings of the National Academy of Sciences of the United States of America, 2011
- Small-Molecule Ligands of Methyl-Lysine Binding ProteinsJournal of Medicinal Chemistry, 2011
- TRIM24 links a non-canonical histone signature to breast cancerNature, 2010
- 53BP1 loss rescues BRCA1 deficiency and is associated with triple-negative and BRCA-mutated breast cancersNature Structural & Molecular Biology, 2010
- Enzymatic and structural insights for substrate specificity of a family of jumonji histone lysine demethylasesNature Structural & Molecular Biology, 2009
- Structural basis for G9a-like protein lysine methyltransferase inhibition by BIX-01294Nature Structural & Molecular Biology, 2009
- The plant homeodomain finger of RAG2 recognizes histone H3 methylated at both lysine-4 and arginine-2Proceedings of the National Academy of Sciences of the United States of America, 2007
- ESET/SETDB1 gene expression and histone H3 (K9) trimethylation in Huntington's diseaseProceedings of the National Academy of Sciences of the United States of America, 2006