Journal
ACS MEDICINAL CHEMISTRY LETTERS
Volume 12, Issue 8, Pages 1308-1317Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.1c00294
Keywords
TAF1; TAF1L; Bromodomain; Epigenetics
Categories
Funding
- GlaxoSmithKline RD, Stevenage
- University of Strathclyde
- EPSRC [EP/S035990/1]
- EPSRC [EP/S035990/1] Funding Source: UKRI
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Selective small molecule bromodomain inhibitors developed by researchers have potential for future development of small molecules to study TAF1(2) biology, with key impact from modulating the basicity of a pendant amine.
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.
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