The Pseudo‐Natural Product Tafbromin Selectively Targets the TAF1 Bromodomain 2

Author:

Patil Sohan1ORCID,Cremosnik Gregor1ORCID,Dötsch Lara12ORCID,Flegel Jana1,Schulte Britta1,Maier Kerstin C.3,Žumer Kristina3,Cramer Patrick3,Janning Petra1,Sievers Sonja1ORCID,Ziegler Slava1ORCID,Waldmann Herbert12ORCID

Affiliation:

1. Max-Planck Institute of Molecular Physiology Department of Chemical Biology Otto-Hahn-Strasse 11 Dortmund 44227 Germany

2. Technical University Dortmund Faculty of Chemistry and Chemical Biology Otto-Hahn-Strasse 6 Dortmund 44227 Germany

3. Max Planck Institute for Multidisciplinary Sciences Department of Molecular Biology Am Fassberg 11 37077 Göttingen Germany

Abstract

AbstractPhenotypic assays detect small‐molecule bioactivity at functionally relevant cellular sites, and inherently cover a variety of targets and mechanisms of action. They can uncover new small molecule‐target pairs and may give rise to novel biological insights. By means of an osteoblast differentiation assay which employs a Hedgehog (Hh) signaling agonist as stimulus and which monitors an endogenous marker for osteoblasts, we identified a pyrrolo[3,4‐g]quinoline (PQ) pseudo‐natural product (PNP) class of osteogenesis inhibitors. The most potent PQ, termed Tafbromin, impairs canonical Hh signaling and modulates osteoblast differentiation through binding to the bromodomain 2 of the TATA‐box binding protein‐associated factor 1 (TAF1). Tafbromin is the most selective TAF1 bromodomain 2 ligand and promises to be an invaluable tool for the study of biological processes mediated by TAF1(2) bromodomains.

Funder

Max-Planck-Gesellschaft

Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung

Publisher

Wiley

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