Discovery of a chemical probe to study implications of BPTF bromodomain inhibition in cellular and in vivo experiments

  • 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.
Author:Paola MartinelliORCiDGND, Otmar Schaaf, Andreas Mantoulidis, Laetitia J. Martin, Julian E. Fuchs, Gerd BaderORCiD, Andreas GollnerORCiD, Bernhard Wolkerstorfer, Catherine Rogers, Esra Balıkçı, Jesse J. Lipp, Nikolai Mischerikow, Sandra Doebel, Thomas Gerstberger, Wolfgang Sommergruber, Kilian HuberORCiDGND, Jark BöttcherORCiDGND
Pubmed Id:
Parent Title (English):ChemMedChem
Place of publication:Weinheim
Document Type:Article
Date of Publication (online):2023/02/06
Date of first Publication:2023/02/06
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2023/07/17
Article Number:e202200686
Page Number:8
First Page:1
Last Page:8
This project received funding from the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement No 875510. The JU receives support from the European Union's Horizon 2020 research and innovation programme and EFPIA and Ontario Institute for Cancer Research, Royal Institution for the Advancement of Learning McGill University, Kungliga Tekniska Hoegskolan, Diamond Light Source Limited. We thank Steffen Steurer for upscaling of BI-7190, Moriz Mayer for compound analytics, Mark Pearson and Manfred Koegl for supervising biological experiments, Darryl B. McConnell for supervising medicinal chemistry.
Data Availability Statement
The authors declare that the data supporting the findings of this study have been deposited in the RCSB Protein Data Bank (PDB; with the accession numbers 8AG2 (BPTF–BI-7190) and 8AHC (BRD9–BI-7189) or are available within the publication and its Supporting Information.
Dewey Decimal Classification:5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie
Licence (German):License LogoCreative Commons - CC BY-NC-ND - Namensnennung - Nicht kommerziell - Keine Bearbeitungen 4.0 International