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Henry RA , Kuo YM , Siegel ZS , Yen TJ , Rhodes J , Taylor EA , Andrews AJ
Discordant Effects of Putative Lysine Acetyltransferase Inhibitors in Biochemical and Living Systems
Cells. 2019 Sep 2;8(9)
PMID: 31480793    PMCID: PMC6770547    URL: https://www.ncbi.nlm.nih.gov/pubmed/31480793
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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.
2073-4409 Henry, Ryan A Kuo, Yin-Ming Siegel, Zarek S Yen, Timothy J Rhodes, Jennifer Taylor, Erika A Andrews, Andrew J R01 GM102503/GM/NIGMS NIH HHS/United States P30 CA006927/CA/NCI NIH HHS/United States Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Switzerland Cells. 2019 Sep 2;8(9). pii: cells8091022. doi: 10.3390/cells8091022.