2. Academic Validation
  3. Design, synthesis and biological evaluation of β-peptoid-capped HDAC inhibitors with anti-neuroblastoma and anti-glioblastoma activity

Design, synthesis and biological evaluation of β-peptoid-capped HDAC inhibitors with anti-neuroblastoma and anti-glioblastoma activity

  • Medchemcomm. 2018 Oct 23;10(7):1109-1115. doi: 10.1039/c8md00454d.
Nina Reßing 1 2,  Viktoria Marquardt 2 3 4 5,  Christoph G W Gertzen 2 6,  Andrea Schöler 1,  Alexander Schramm 7,  Thomas Kurz 2,  Holger Gohlke 2 6,  Achim Aigner 8,  Marc Remke 3 4 5,  Finn K Hansen 1 2
Affiliations

Affiliations

  • 1 Pharmaceutical/Medicinal Chemistry , Institute of Pharmacy , Leipzig University , Medical Faculty , Brüderstr. 34 , 04103 Leipzig , Germany . Email: finn.hansen@medizin.uni-leipzig.de.
  • 2 Institute for Pharmaceutical and Medicinal Chemistry , Heinrich Heine University Düsseldorf , Universitätsstr. 1 , 40225 Düsseldorf , Germany.
  • 3 Department of Pediatric Oncology , Hematology, and Clinical Immunology, Medical Faculty , Heinrich-Heine-University , Moorenstr. 5 , 40225 Düsseldorf , Germany.
  • 4 Department of Neuropathology , Medical Faculty , Heinrich-Heine-University , Moorenstr. 5 , 40225 Düsseldorf , Germany.
  • 5 Division of Pediatric Neuro-Oncogenomics , German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK) , Partner site Essen/Düsseldorf , Moorenstr. 5 , 40225 Düsseldorf , Germany.
  • 6 John von Neumann Institute for Computing (NIC) , Jülich Supercomputing Centre (JSC) and Institute for Complex Systems - Structural Biochemistry (ICS-6) , Forschungszentrum Jülich GmbH , 52425 Jülich , Germany.
  • 7 Department of Pediatric Oncology and Hematology , University Children's Hospital Essen , University of Duisburg-Essen , Hufelandstr. 55 , 45122 Essen , Germany.
  • 8 Rudolf-Boehm-Institute for Pharmacology and Toxicology , Independent Division for Clinical Pharmacology , Leipzig University , Medical Faculty , Härtelstr. 16-18 , 04107 Leipzig , Germany.
PMID: 31391882 DOI: 10.1039/c8md00454d
Abstract

Histone deacetylases (HDACs) have been identified as promising epigenetic drug targets for the treatment of neuroblastoma and glioblastoma. In this work, we have rationally designed a novel class of peptoid-based histone deacetylase inhibitors (HDACi). A mini library of β-peptoid-capped HDACi was synthesized using a four-step protocol. All compounds were screened in biochemical assays for their inhibition of HDAC1 and HDAC6 and docking studies were performed to rationalize the observed selectivity profile. The synthesized compounds were further examined for tumor cell-inhibitory activity against a panel of neuroblastoma and glioblastoma cell lines. In particular, non-selective compounds with potent activity against HDAC1 and HDAC6 showed strong antiproliferative effects. The most promising HDACi, compound 6i, displayed submicromolar tumor cell-inhibitory potential (IC50: 0.21-0.67 μM) against all five Cancer cell lines investigated and exceeded the activity of the FDA-approved HDACi vorinostat.

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