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
  • 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.

Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-139181
    NR160
    98.9%, HDAC6 Inhibitor
    target: HDAC
    Research Areas: Cancer