2. Academic Validation
  3. 4-Acyl Pyrrole Capped HDAC Inhibitors: A New Scaffold for Hybrid Inhibitors of BET Proteins and Histone Deacetylases as Antileukemia Drug Leads

4-Acyl Pyrrole Capped HDAC Inhibitors: A New Scaffold for Hybrid Inhibitors of BET Proteins and Histone Deacetylases as Antileukemia Drug Leads

  • J Med Chem. 2021 Oct 14;64(19):14620-14646. doi: 10.1021/acs.jmedchem.1c01119.
Linda Schäker-Hübner 1,  Robin Warstat 2,  Heinz Ahlert 3,  Pankaj Mishra 4,  Fabian B Kraft 1 5,  Julian Schliehe-Diecks 3,  Andrea Schöler 1,  Arndt Borkhardt 3,  Bernhard Breit 2,  Sanil Bhatia 3,  Martin Hügle 6,  Stefan Günther 4,  Finn K Hansen 1 5
Affiliations

Affiliations

  • 1 Institut für Wirkstoffentwicklung, Medizinische Fakultät, Universität Leipzig, Brüderstraße 34, D-04103 Leipzig, Germany.
  • 2 Institut für Organische Chemie, Albert-Ludwigs-Universität Freiburg, Albertstraße 21, D-79104 Freiburg, Germany.
  • 3 Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich-Heine University Düsseldorf, Moorenstraße 5, D-40225 Düsseldorf, Germany.
  • 4 Institut für Pharmazeutische Wissenschaften, Albert-Ludwigs-Universität Freiburg, Hermann-Herder-Strasse 9, D-79104 Freiburg, Germany.
  • 5 Abteilung für Pharmazeutische und Zellbiologische Chemie, Pharmazeutisches Institut, Universität Bonn, An der Immenburg 4, D-53121 Bonn, Germany.
  • 6 Institut für Biochemie, Albert-Ludwigs-Universität Freiburg, Albertstraße 21, D-79104 Freiburg, Germany.
PMID: 34582215 DOI: 10.1021/acs.jmedchem.1c01119
Abstract

Multitarget drugs are an emerging alternative to combination therapies. In three iterative cycles of design, synthesis, and biological evaluation, we developed a novel type of potent hybrid inhibitors of bromodomain, and extra-terminal (BET) proteins and histone deacetylases (HDACs) based on the BET inhibitor XD14 and well-established HDAC inhibitors. The most promising new hybrids, 49 and 61, displayed submicromolar inhibitory activity against HDAC1-3 and 6, and BRD4(1), and possess potent antileukemia activity. 49 induced Apoptosis more effectively than the combination of ricolinostat and birabresib (1:1). The most balanced dual inhibitor, 61, induced significantly more Apoptosis than the related control compounds 62 (no BRD4(1) affinity) and 63 (no HDAC inhibition) as well as the 1:1 combination of both. Additionally, 61 was well tolerated in an in vivo zebrafish toxicity model. Overall, our data suggest an advantage of dual HDAC/BET inhibitors over the combination of two single targeted compounds.

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