Open AccessOptimization of Naphthyridones into Selective TATA-Binding Protein Associated Factor 1 (TAF1) Bromodomain Inhibitors
Author(s) -
Michael A. Clegg,
Natalie H. Theodoulou,
Paul Bamborough,
Chunwa Chung,
Peter D. Craggs,
Emmanuel H. Demont,
Laurie J. Gordon,
Gemma M. Liwicki,
Alex Phillipou,
Nicholas C. O. Tomkinson,
Rab K. Prinjha,
P. G. Humphreys
Publication year - 2021
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.1c00294
Subject(s) - bromodomain , taf1 , epigenetics , computational biology , small molecule , chemistry , biochemistry , biology , microbiology and biotechnology , gene , gene expression , promoter
Bromodomain containing proteins and the acetyl-lysine binding bromodomains contained therein are increasingly attractive targets for the development of novel epigenetic therapeutics. To help validate this target class and unravel the complex associated biology, there has been a concerted effort to develop selective small molecule bromodomain inhibitors. Herein we describe the structure-based efforts and multiple challenges encountered in optimizing a naphthyridone template into selective TAF1(2) bromodomain inhibitors which, while unsuitable as chemical probes themselves, show promise for the future development of small molecules to interrogate TAF1(2) biology. Key to this work was the introduction and modulation of the basicity of a pendant amine which had a substantial impact on not only bromodomain selectivity but also cellular target engagement.