2. Academic Validation
  3. Solid-Phase Synthesis of Cereblon-Recruiting Selective Histone Deacetylase 6 Degraders (HDAC6 PROTACs) with Antileukemic Activity

Solid-Phase Synthesis of Cereblon-Recruiting Selective Histone Deacetylase 6 Degraders (HDAC6 PROTACs) with Antileukemic Activity

  • J Med Chem. 2022 Dec 22;65(24):16860-16878. doi: 10.1021/acs.jmedchem.2c01659.
Laura Sinatra 1,  Jing Yang 2 3,  Julian Schliehe-Diecks 2,  Niklas Dienstbier 2,  Melina Vogt 2,  Philip Gebing 2,  Luisa M Bachmann 1,  Melf Sönnichsen 2,  Thomas Lenz 4,  Kai Stühler 5,  Andrea Schöler 1,  Arndt Borkhardt 2,  Sanil Bhatia 2,  Finn K Hansen 6
Affiliations

Affiliations

  • 1 Institute for Drug Discovery, Medical Faculty, Leipzig University, Brüderstrasse 34, 04103 Leipzig, Germany.
  • 2 Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich Heine University Düsseldorf, Moorenstrasse 5, 40225 Düsseldorf, Germany.
  • 3 Department of Medicine, Yangzhou Polytechnic College, West Wenchang Road 458, Yangzhou, 225009, P.R. China.
  • 4 Molecular Proteomics Laboratory, Biological Medical Research Center, Heinrich-Heine-University Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany.
  • 5 Institute for Molecular Medicine, Proteome Research, University Hospital and Medical Faculty, Hein-rich-Heine-University Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany.
  • 6 Pharmaceutical Institute, Department of Pharmaceutical and Cell Biological Chemistry, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany.
PMID: 36473103 DOI: 10.1021/acs.jmedchem.2c01659
Abstract

In this work, we utilized the proteolysis targeting chimera (PROTAC) technology to achieve the chemical knock-down of histone deacetylase 6 (HDAC6). Two series of cereblon-recruiting PROTACs were synthesized via a solid-phase parallel synthesis approach, which allowed the rapid preparation of two HDAC6 Degrader mini libraries. The PROTACs were either based on an unselective vorinostat-like HDAC ligand or derived from a selective HDAC6 Inhibitor. Notably, both PROTAC series demonstrated selective degradation of HDAC6 in leukemia cell lines. The best degraders from each series (denoted A6 and B4) were capable of degrading HDAC6 via ternary complex formation and the ubiquitin-proteasome pathway, with DC50 values of 3.5 and 19.4 nM, respectively. PROTAC A6 demonstrated promising antiproliferative activity via inducing Apoptosis in myeloid leukemia cell lines. These findings highlight the potential of this series of degraders as effective pharmacological tools for the targeted degradation of HDAC6.

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