2. Academic Validation
  3. A novel pan-selective bromodomain inhibitor for epigenetic drug design

A novel pan-selective bromodomain inhibitor for epigenetic drug design

  • Eur J Med Chem. 2023 Mar 5;249:115139. doi: 10.1016/j.ejmech.2023.115139.
Robin Warstat 1,  Mehrosh Pervaiz 2,  Pierre Regenass 1,  Marius Amann 3,  Karin Schmidtkunz 4,  Oliver Einsle 5,  Manfred Jung 4,  Bernhard Breit 1,  Martin Hügle 6,  Stefan Günther 2
Affiliations

Affiliations

  • 1 Institut für Organische Chemie, Albert-Ludwigs-Universität Freiburg, Albertstr. 21, D-79104, Freiburg, Germany.
  • 2 Institut für Pharmazeutische Wissenschaften, Albert-Ludwigs-Universität Freiburg, Hermann-Herder-Str. 9, D-79104, Freiburg, Germany.
  • 3 Institut für Pharmazeutische Wissenschaften, Albert-Ludwigs-Universität Freiburg, Hermann-Herder-Str. 9, D-79104, Freiburg, Germany; Institut für Biochemie, Albert-Ludwigs-Universität Freiburg, Albertstr. 21, D-79104, Freiburg, Germany.
  • 4 Institut für Pharmazeutische Wissenschaften, Albert-Ludwigs-Universität Freiburg, Albertstr. 25, D-79104, Freiburg, Germany.
  • 5 Institut für Biochemie, Albert-Ludwigs-Universität Freiburg, Albertstr. 21, D-79104, Freiburg, Germany.
  • 6 Institut für Pharmazeutische Wissenschaften, Albert-Ludwigs-Universität Freiburg, Hermann-Herder-Str. 9, D-79104, Freiburg, Germany; Institut für Biochemie, Albert-Ludwigs-Universität Freiburg, Albertstr. 21, D-79104, Freiburg, Germany. Electronic address: martin.huegle@pharmazie.uni-freiburg.de.
PMID: 36736153 DOI: 10.1016/j.ejmech.2023.115139
Abstract

For a long time, the development of bromodomain (BD) inhibitors (BDi) was almost exclusively related to the BET family. More recently, BDi for BDs outside the BET family have also been developed. Here we present a novel pan-BDi with micromolar affinities to various BDs, and nanomolar affinities to representatives of BD families I, II (Bromodomain and Extra-Terminal Domain (BET) family), III, and IV. The inhibitor shows a broad activity profile with nanomolar growth inhibition (GI50) values on various Cancer cell lines. Subsequently, we were able to control the selectivity of the inhibitor by simple modifications and turned it into a highly selective BRD9 Inhibitor.

Keywords

Bromodomain; Drug design; Epigenetics; MPM6; Pan-inhibitor.

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