2. Academic Validation
  3. Electrophilic MiniFrags Revealed Unprecedented Binding Sites for Covalent HDAC8 Inhibitors

Electrophilic MiniFrags Revealed Unprecedented Binding Sites for Covalent HDAC8 Inhibitors

  • J Med Chem. 2024 Jan 11;67(1):572-585. doi: 10.1021/acs.jmedchem.3c01779.
Aaron B Keeley 1 2 3,  Aleksandra Kopranovic 4,  Vincenzo Di Lorenzo 1 2 3,  Péter Ábrányi-Balogh 1 2 3,  Niklas Jänsch 4,  Linh N Lai 4,  László Petri 1 2 3,  Zoltán Orgován 1 2 3,  Daniel Pölöske 5,  Anna Orlova 5,  András György Németh 1 2 3,  Charlotte Desczyk 4,  Tímea Imre 1 6,  Dávid Bajusz 1 2 3,  Richard Moriggl 5,  Franz-Josef Meyer-Almes 4,  György M Keserü 1 2 3
Affiliations

Affiliations

  • 1 Medicinal Chemistry Research Group, Research Centre for Natural Sciences, Magyar tudósok krt 2, H-1117 Budapest, Hungary.
  • 2 Department of Organic Chemistry and Technology, Faculty of Chemical Technology and Biotechnology, Budapest University of Technology and Economics, Müegyetem rkp. 3., H-1111 Budapest, Hungary.
  • 3 National Laboratory for Drug Research and Development, H-1117 Budapest, Hungary.
  • 4 Department of Chemical Engineering and Biotechnology, University of Applied Sciences Darmstadt, Haardtring 100, 64295 Darmstadt, Germany.
  • 5 Institute of Animal Breeding and Genetics, University of Veterinary Medicine, 1210 Vienna, Austria.
  • 6 MS Metabolomics Research Group, Research Centre for Natural Sciences, Magyar tudósok krt 2, H-1117 Budapest, Hungary.
PMID: 38113354 DOI: 10.1021/acs.jmedchem.3c01779
Abstract

Screening of ultra-low-molecular weight ligands (MiniFrags) successfully identified viable chemical starting points for a variety of drug targets. Here we report the electrophilic analogues of MiniFrags that allow the mapping of potential binding sites for covalent inhibitors by biochemical screening and mass spectrometry. Small electrophilic heterocycles and their N-quaternized analogues were first characterized in the glutathione assay to analyze their electrophilic reactivity. Next, the library was used for systematic mapping of potential covalent binding sites available in human histone deacetylase 8 (HDAC8). The covalent labeling of HDAC8 cysteines has been proven by tandem mass spectrometry measurements, and the observations were explained by mutating HDAC8 cysteines. As a result, screening of electrophilic MiniFrags identified three potential binding sites suitable for the development of allosteric covalent HDAC8 inhibitors. One of the hit fragments was merged with a known HDAC8 Inhibitor fragment using different linkers, and the linker length was optimized to result in a lead-like covalent inhibitor.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-163143
    HDAC8 Inhibitor