4-Pyridone-3-carboxylic acid as a benzoic acid bioisostere: Design, synthesis, and evaluation of EP300/CBP histone acetyltransferase inhibitors. (1st November 2021)

• Record Type: Journal Article
• Authors: Kanada, Ryutaro; Suzuki, Takashi; Murata, Takeshi; Miyazaki, Masaki; Shimada, Takashi; Kuroha, Mutsumi; Minami, Megumi; Higuchi, Saito; Tominaga, Yuichi; Naito, Hiroyuki
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 51(2021)
• Publication Date: 2021-11-01
• Subjects: Drug discovery -- Virtual screening -- Histone acetyltransferase -- EP300/CBP selective inhibitor -- Bioisosterism; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2021.128358
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: Histone acetyltransferases (HATs) play a crucial role in post-translational modification. Among them, overexpression, mutation, or hyperfunction of EP300/CBP has been associated with various cancers. In this study, we identified the novel compound 2-chloro-5-[5-[( E )-[1-(3-chlorophenyl)-3-methyl-5-oxo-pyrazol-4-ylidene]methyl]-2-furyl]benzoic acid (1 ) as an EP300 HAT inhibitor via virtual screening. Further research has been focused on the design, synthesis, and in vitro biological evaluation of virtual hit derivatives. The studies revealed that 4-pyridone-3-carboxylic acid derivatives exhibited bioisosterism of benzoic acid. Replacement proved effective, providing compounds with similar EP300 HAT-inhibitory activity and improved cell growth-inhibitory activity compared to the benzoic acid analogs. Through these studies, we identified a potent and selective EP300/CBP HAT inhibitor.