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Discovery of an Unexpected Similarity in Ligand Binding Between BRD4 and PPARγ

preprint
submitted on 29.12.2019 and posted on 31.12.2019 by Lina Humbeck, Jette Pretzel, Saskia Spitzer, Oliver Koch
Knowledge about interrelationships between different proteins is crucial in fundamental research for the elucidation of protein networks and pathways. Furthermore, it is especially critical in chemical biology to identify further key regulators of a disease and to take advantage of polypharmacology effects. A comprehensive scaffold-based analysis uncovered an unexpected relationship between bromodomain-containing protein 4 (BRD4) and peroxisome-proliferator activated receptor gamma (PPARγ). They are both important drug targets for cancer therapy and many more important diseases. Both proteins share binding site similarities near a common hydrophobic subpocket which should allow the design of a polypharmacology-based ligand targeting both proteins. Such a dual-BRD4-PPARγ-modulator could show synergistic effects with a higher efficacy or delayed resistance development in, for example, cancer therapy. Thereon, a complex structure of sulfasalazine was obtained that involves two bromodomains and could be a potential starting point for the design of a bivalent BRD4 inhibitor.

Funding

DFG - SPP 1736 - Algorithms for Big Data - KO 4689/2-1

BMBF - Grant No. 1316053

History

Email Address of Submitting Author

oliver.koch@agkoch.de

Institution

TU Dortmund University

Country

Germany

ORCID For Submitting Author

0000-0001-9228-217X

Declaration of Conflict of Interest

The authors declare no conflict of interest.

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