2. Academic Validation
  3. Multicomponent Synthesis, Binding Mode, and Structure-Activity Relationship of Selective Histone Deacetylase 6 (HDAC6) Inhibitors with Bifurcated Capping Groups

Multicomponent Synthesis, Binding Mode, and Structure-Activity Relationship of Selective Histone Deacetylase 6 (HDAC6) Inhibitors with Bifurcated Capping Groups

  • J Med Chem. 2020 Sep 24;63(18):10339-10351. doi: 10.1021/acs.jmedchem.9b01888.
Nina Reßing 1 2,  Melf Sönnichsen 3,  Jeremy D Osko 4,  Andrea Schöler 1,  Julian Schliehe-Diecks 3,  Alexander Skerhut 5,  Arndt Borkhardt 3,  Julia Hauer 6,  Matthias U Kassack 5,  David W Christianson 4,  Sanil Bhatia 3,  Finn K Hansen 1 2
Affiliations

Affiliations

  • 1 Institute for Drug Discovery, Medical Faculty, Leipzig University, Brüderstr. 34, 04103 Leipzig, Germany.
  • 2 Pharmaceutical and Cell Biological Chemistry, Pharmaceutical Institute, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany.
  • 3 Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich Heine University Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany.
  • 4 Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia, Pennsylvania 19104-6323, United States.
  • 5 Institute for Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Universitätsstraße 1, 40225 Düsseldorf, Germany.
  • 6 Department of Pediatrics, Pediatric Hematology and Oncology, University Hospital Carl Gustav Carus, Dresden University of Technology, Fetscherstr. 74, 01307 Dresden, Germany.
PMID: 32803970 DOI: 10.1021/acs.jmedchem.9b01888
Abstract

Histone deacetylase 6 (HDAC6) is an emerging target for the treatment of Cancer, neurodegenerative diseases, inflammation, and Other Diseases. Here, we present the multicomponent synthesis and structure-activity relationship of a series of tetrazole-based HDAC6 inhibitors. We discovered the hit compound NR-160 by investigating the inhibition of recombinant HDAC enzymes and protein acetylation. A cocrystal structure of HDAC6 complexed with NR-160 disclosed that the steric complementarity of the bifurcated capping group of NR-160 to the L1 and L2 loop pockets may be responsible for its HDAC6-selective inhibition. While NR-160 displayed only low cytotoxicity as a single agent against leukemia cell lines, it augmented the Apoptosis induction of the Proteasome Inhibitor bortezomib in combination experiments significantly. Furthermore, a combinatorial high-throughput drug screen revealed significantly enhanced cytotoxicity when NR-160 was used in combination with epirubicin and daunorubicin. The synergistic effect in combination with bortezomib and anthracyclines highlights the potential of NR-160 in combination therapies.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-139181
    HDAC6 Inhibitor