4-Acyl Pyrrole Derivatives Yield Novel Vectors for Designing Inhibitors of the Acetyl-Lysine Recognition Site of BRD4(1)

Martin Hügle, Xavier Lucas, Gerhard Weitzel, Dmytro Ostrovskyi, Bernhard Breit, Stefan Gerhardt, Oliver Einsle, Stefan Günther, Daniel Wohlwend (Lead / Corresponding author)

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31 Citations (Scopus)

Abstract

Several human diseases, including cancer, show altered signaling pathways resulting from changes in the activity levels of epigenetic modulators. In the past few years, small-molecule inhibitors against specific modulators, including the bromodomain and extra-terminal (BET) bromodomain family of acetylation readers, have shown early promise in the treatment of the genetically defined midline carcinoma and hematopoietic malignancies. We have recently developed a novel potent inhibitor of BET proteins, 1 (XD14[ Angew. Chem., Int. Ed. 2013, 52, 14055 ]), which exerts a strong inhibitory potential on the proliferation of specific leukemia cell lines. In the study presented here, we designed analogues of 1 to study the potential of substitutions on the 4-acyl pyrrole backbone to occupy additional sites within the substrate recognition site of BRD4(1). The compounds were profiled using ITC, DSF, and X-ray crystallography. We could introduce several substitutions that address previously untargeted areas of the substrate recognition site. This work may substantially contribute to the development of therapeutics with increased target specificity against BRD4-related malignancies.

Original languageEnglish
Pages (from-to)1518-1530
Number of pages13
JournalJournal of Medicinal Chemistry
Volume59
Issue number4
Early online date5 Jan 2016
DOIs
Publication statusPublished - 25 Feb 2016

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    Hügle, M., Lucas, X., Weitzel, G., Ostrovskyi, D., Breit, B., Gerhardt, S., Einsle, O., Günther, S., & Wohlwend, D. (2016). 4-Acyl Pyrrole Derivatives Yield Novel Vectors for Designing Inhibitors of the Acetyl-Lysine Recognition Site of BRD4(1). Journal of Medicinal Chemistry, 59(4), 1518-1530. https://doi.org/10.1021/acs.jmedchem.5b01267