2. Academic Validation
  3. Discovery of the First-in-Class Dual Histone Deacetylase-Proteasome Inhibitor

Discovery of the First-in-Class Dual Histone Deacetylase-Proteasome Inhibitor

  • J Med Chem. 2018 Nov 21;61(22):10299-10309. doi: 10.1021/acs.jmedchem.8b01487.
Sanil Bhatia 1,  Viktoria Krieger 2,  Michael Groll 3,  Jeremy D Osko 4,  Nina Reßing 5,  Heinz Ahlert 1,  Arndt Borkhardt 1,  Thomas Kurz 2,  David W Christianson 4,  Julia Hauer 1,  Finn K Hansen 5
Affiliations

Affiliations

  • 1 Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty , Heinrich Heine University Düsseldorf , Moorenstrasse 5 , 40225 Düsseldorf , Germany.
  • 2 Institute for Pharmaceutical and Medicinal Chemistry , Heinrich Heine University Düsseldorf , Universitätsstrasse 1 , 40225 Düsseldorf , Germany.
  • 3 Center for Integrated Protein Science at the Department Chemie, Lehrstuhl für Biochemie , Technische Universität München , Lichtenbergstrasse 4 , 85747 Garching , Germany.
  • 4 Roy and Diana Vagelos Laboratories, Department of Chemistry , University of Pennsylvania , 231 South 34th Street , Philadelphia , Pennsylvania 19104-6323 , United States.
  • 5 Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Medical Faculty , Leipzig University , Brüderstraße 34 , 04103 Leipzig , Germany.
PMID: 30365892 DOI: 10.1021/acs.jmedchem.8b01487
Abstract

Dual- or multitarget drugs have emerged as a promising alternative to combination therapies. Proteasome inhibitors (PIs) possess synergistic activity with histone deacetylase (HDAC) inhibitors due to the simultaneous blockage of the ubiquitin degradation and aggresome pathways. Here, we present the design, synthesis, binding modes, and Anticancer properties of RTS-V5 as the first-in-class dual HDAC-proteasome ligand. The inhibition of both targets was confirmed by biochemical and cellular assays as well as X-ray crystal structures of the 20S Proteasome and HDAC6 complexed with RTS-V5. Cytotoxicity assays with leukemia and multiple myeloma cell lines as well as therapy refractory primary patient-derived leukemia cells demonstrated that RTS-V5 possesses potent and selective Anticancer activity. Our results will thus guide the structure-based optimization of dual HDAC-proteasome inhibitors for the treatment of hematological malignancies.

Figures
Products