8AG2

Crystal structure of the BPTF bromodomain in complex with BI-7190

Summary for 8AG2

• Entry DOI: 10.2210/pdb8ag2/pdb
• Descriptor: Nucleosome-remodeling factor subunit BPTF, 5-[3-methoxy-4-[1-(4-methylpiperazin-1-yl)cyclopropyl]phenyl]-1,3,4-trimethyl-pyridin-2-one (3 entities in total)
• Functional Keywords: bromodomain, inhibitor, complex, protein binding
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 14618.65

Authors

Bader, G.,Boettcher, J.,Wolkerstorfer, B. (deposition date: 2022-07-19, release date: 2022-08-31, Last modification date: 2024-02-07)

Primary citation

Martinelli, P.,Schaaf, O.,Mantoulidis, A.,Martin, L.J.,Fuchs, J.E.,Bader, G.,Gollner, A.,Wolkerstorfer, B.,Rogers, C.,Balikci, E.,Lipp, J.J.,Mischerikow, N.,Doebel, S.,Gerstberger, T.,Sommergruber, W.,Huber, K.V.M.,Bottcher, J.
Discovery of a Chemical Probe to Study Implications of BPTF Bromodomain Inhibition in Cellular and in vivo Experiments.
Chemmedchem, 18:e202200686-e202200686, 2023

PubMed Abstract: The bromodomain and PHD-finger containing transcription factor (BPTF) is part of the nucleosome remodeling factor (NURF) complex and has been implicated in multiple cancer types. Here, we report the discovery of a potent and selective chemical probe targeting the bromodomain of BPTF with an attractive pharmacokinetic profile enabling cellular and in vivo experiments in mice. Microarray-based transcriptomics in presence of the probe in two lung cancer cell lines revealed only minor effects on the transcriptome. Profiling against a panel of cancer cell lines revealed that the antiproliferative effect does not correlate with BPTF dependency score in depletion screens. Both observations and the multi-domain architecture of BPTF suggest that depleting the protein by proteolysis targeting chimeras (PROTACs) could be a promising strategy to target cancer cell proliferation. We envision that the presented chemical probe and the related negative control will enable the research community to further explore scientific hypotheses with respect to BPTF bromodomain inhibition.

PubMed: 36649575
DOI: 10.1002/cmdc.202200686

Experimental method

X-RAY DIFFRACTION (1.025 Å)