Discovery of spirohydantoins as selective, orally bioavailable inhibitors of p300/CBP histone acetyltransferases.

Abstract

p300 and CREB-binding protein (CBP) are essential for a multitude of cellular processes. Dysregulation of p300/CBP histone acetyltransferase activity is linked to a broad spectrum of human diseases including cancers. A novel drug-like spirohydantoin (21) has been discovered as a selective orally bioavailable inhibitor of p300/CBP histone acetyltransferase. Lead compound 21 is more potent than the first-in-class lead A-485 in both enzymatic and cellular assays and lacks the off-target inhibition of dopamine and serotonin transporters, that was observed with A-485.

• Authors: Zhiqin Ji, Richard F Clark, Vikram Bhat, T Matthew Hansen, Loren M Lasko, Kenneth D Bromberg, Vlasios Manaves, Mikkel Algire, Ruth Martin, Wei Qiu, Maricel Torrent, Clarissa G Jakob, Hong Liu, Philip A Cole, Ronen Marmorstein, Edward A Kesicki, Albert Lai, Michael R Michaelides
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 39 Pg. 127854 (05 01 2021) ISSN: 1464-3405 [Electronic] England
• PMID: 33631370 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2021 Elsevier Ltd. All rights reserved.

Chemical References

• Enzyme Inhibitors
• Hydantoins
• Spiro Compounds
• CREB-Binding Protein
• CREBBP protein, human
• E1A-Associated p300 Protein
• EP300 protein, human

Topics

• Administration, Oral
• Biological Availability
• CREB-Binding Protein (antagonists & inhibitors, metabolism)
• Dose-Response Relationship, Drug
• Drug Discovery
• E1A-Associated p300 Protein (antagonists & inhibitors, metabolism)
• Enzyme Inhibitors (administration & dosage, metabolism, pharmacology)
• Humans
• Hydantoins (administration & dosage, metabolism, pharmacology)
• Molecular Structure
• Spiro Compounds (administration & dosage, metabolism, pharmacology)
• Structure-Activity Relationship