7P4S

BROMODOMAIN OF HUMAN TAF1 (2) WITH naphthyridinone compound

Summary for 7P4S

• Entry DOI: 10.2210/pdb7p4s/pdb
• Descriptor: Isoform 2a of Transcription initiation factor TFIID subunit 1, 8-[[1-(3-azanylpropyl)piperidin-4-yl]amino]-5-[5-(hydroxymethyl)pyridin-3-yl]-3-methyl-1~{H}-1,7-naphthyridin-2-one (3 entities in total)
• Functional Keywords: second bromodomain of taf1, inhibitor-bound, complex, transcription
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 16697.83

Authors

Chung, C. (deposition date: 2021-07-13, release date: 2021-10-13, Last modification date: 2024-01-31)

Primary citation

Clegg, M.A.,Theodoulou, N.H.,Bamborough, P.,Chung, C.W.,Craggs, P.D.,Demont, E.H.,Gordon, L.J.,Liwicki, G.M.,Phillipou, A.,Tomkinson, N.C.O.,Prinjha, R.K.,Humphreys, P.G.
Optimization of Naphthyridones into Selective TATA-Binding Protein Associated Factor 1 (TAF1) Bromodomain Inhibitors.
Acs Med.Chem.Lett., 12:1308-1317, 2021

PubMed Abstract: 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.

PubMed: 34413961
DOI: 10.1021/acsmedchemlett.1c00294

Experimental method

X-RAY DIFFRACTION (2.17 Å)