PUBLICATION
Discordant Effects of Putative Lysine Acetyltransferase Inhibitors in Biochemical and Living Systems
- Authors
- Henry, R.A., Kuo, Y.M., Siegel, Z.S., Yen, T.J., Rhodes, J., Taylor, E.A., Andrews, A.J.
- ID
- ZDB-PUB-190905-2
- Date
- 2019
- Source
- Cells 8(9): (Journal)
- Registered Authors
- Rhodes, Jennifer
- Keywords
- KAT, drug screen, epigenetics, histones, mass spectrometry, p300
- MeSH Terms
-
- Binding Sites
- Zebrafish
- Toxicity Tests/standards
- Lysine Acetyltransferases/antagonists & inhibitors
- Lysine Acetyltransferases/chemistry*
- Lysine Acetyltransferases/metabolism
- Embryo, Nonmammalian/drug effects
- Histones/metabolism
- Animals
- Cell Line
- Enzyme Inhibitors/pharmacology*
- Enzyme Inhibitors/toxicity
- Protein Binding
- Acetylation
- PubMed
- 31480793 Full text @ Cells
Citation
Henry, R.A., Kuo, Y.M., Siegel, Z.S., Yen, T.J., Rhodes, J., Taylor, E.A., Andrews, A.J. (2019) Discordant Effects of Putative Lysine Acetyltransferase Inhibitors in Biochemical and Living Systems. Cells. 8(9):.
Abstract
Lysine acetyltransferases (KATs) are exquisitely fine-tuned to target specific lysine residues on many proteins, including histones, with aberrant acetylation at distinct lysines implicated in different pathologies. However, researchers face a lack of molecular tools to probe the importance of site-specific acetylation events in vivo. Because of this, there can be a disconnect between the predicted in silico or in vitro effects of a drug and the actual observable in vivo response. We have previously reported on how an in vitro biochemical analysis of the site-specific effects of the compound C646 in combination with the KAT p300 can accurately predict changes in histone acetylation induced by the same compound in cells. Here, we build on this effort by further analyzing a number of reported p300 modulators, while also extending the analysis to correlate the effects of these drugs to developmental and phenotypical changes, utilizing cellular and zebrafish model systems. While this study demonstrates the utility of biochemical models as a starting point for predicting in vivo activity of multi-site targeting KATs, it also highlights the need for the development of new enzyme inhibitors that are more specific to the regulation of KAT activity in vivo.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping