6P38

Crystal Structure Analysis of TAF1 Bromodomain

Summary for 6P38

• Entry DOI: 10.2210/pdb6p38/pdb
• Descriptor: Transcription initiation factor TFIID subunit 1, 4-{[(3R)-4-cyclopentyl-1,3-dimethyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-6-yl]amino}-N-(1-methylpiperidin-4-yl)-3-[(propan-2-yl)oxy]benzamide (2 entities in total)
• Functional Keywords: kinase, bromodomain, inhibitor, transcription, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 16417.51

Authors

Seo, H.-S.,Dhe-Paganon, S. (deposition date: 2019-05-23, release date: 2020-05-27, Last modification date: 2023-10-11)

Primary citation

Remillard, D.,Buckley, D.L.,Seo, H.S.,Ferguson, F.M.,Dhe-Paganon, S.,Bradner, J.E.,Gray, N.S.
Dual Inhibition of TAF1 and BET Bromodomains from the BI-2536 Kinase Inhibitor Scaffold.
Acs Med.Chem.Lett., 10:1443-1449, 2019

PubMed Abstract: Recent reports have highlighted the dual bromodomains of TAF1 (TAF1(1,2)) as synergistic with BET inhibition in cellular cancer models, engendering interest in TAF/BET polypharmacology. Here, we examine structure activity relationships within the BI-2536 PLK1 kinase inhibitor scaffold, previously reported to bind BRD4. We examine binding by this ligand to TAF1(2) and apply structure guided design strategies to discriminate binding to both the PLK1 kinase and BRD4(1) bromodomain while retaining activity on TAF1(2). Through this effort we discover potent dual inhibitors of TAF1(2)/BRD4(1), as well as biased derivatives showing marked TAF1 selectivity. We resolve X-ray crystallographic data sets to examine the mechanisms of the observed TAF1 selectivity and to provide a resource for further development of this scaffold.

PubMed: 31620231
DOI: 10.1021/acsmedchemlett.9b00243

Experimental method

X-RAY DIFFRACTION (2.8 Å)