2. Academic Validation
  3. Beyond the BET Family: Targeting CBP/p300 with 4-Acyl Pyrroles

Beyond the BET Family: Targeting CBP/p300 with 4-Acyl Pyrroles

  • Angew Chem Int Ed Engl. 2017 Oct 2;56(41):12476-12480. doi: 10.1002/anie.201705516.
Martin Hügle 1,  Xavier Lucas 2,  Dmytro Ostrovskyi 3,  Pierre Regenass 3,  Stefan Gerhardt 1,  Oliver Einsle 1 4 5,  Mirjam Hau 6,  Manfred Jung 6,  Bernhard Breit 4 3,  Stefan Günther 6 4,  Daniel Wohlwend 1
Affiliations

Affiliations

  • 1 Institut für Biochemie, Albert-Ludwigs-Universität Freiburg, Albertstrasse 21, 79104, Freiburg, Germany.
  • 2 School of Life Sciences, Division of Biological Chemistry and Drug Discovery, University of Dundee, James Black Centre, Dow Street, Dundee, DD1 5EH, UK.
  • 3 Institut für Organische Chemie, Albert-Ludwigs-Universität Freiburg, Albertstrasse 21, 79104, Freiburg, Germany.
  • 4 Freiburg Institute for Advanced Studies (FRIAS), Albert-Ludwigs-Universität Freiburg, Albertstrasse 21, 79104, Freiburg, Germany.
  • 5 BIOSS Centre for Biological Signalling Studies, Albert-Ludwigs-Universität Freiburg, Albertstr. 21, 79104, Freiburg, Germany.
  • 6 Institut für Pharmazeutische Wissenschaften, Albert-Ludwigs-Universität Freiburg, Hermann-Herder-Strasse 9, 79104, Freiburg, Germany.
PMID: 28766825 DOI: 10.1002/anie.201705516
Abstract

Bromodomain and extra-terminal domain (BET) inhibitors are widely used both as chemical tools to study the biological role of their targets in living organisms and as candidates for drug development against several Cancer variants and human disorders. However, non-BET bromodomains such as those in p300 and CBP are less studied. XDM-CBP is a highly potent and selective inhibitor for the bromodomains of CBP and p300 derived from a pan-selective BET BRD-binding fragment. Along with X-ray crystal-structure analysis and thermodynamic profiling, XDM-CBP was used in screenings of several Cancer cell lines in vitro to study its inhibitory potential on Cancer cell proliferation. XDM-CBP is demonstrated to be a potent and selective CBP/p300 inhibitor that acts on specific Cancer cell lines, in particular malignant melanoma, breast Cancer, and leukemia.

Keywords

4-acyl pyrroles; CBP; bromodomains; drug discovery; p300.

Figures
Products