Electrophilic MiniFrags Revealed Unprecedented Binding Sites for Covalent HDAC8 Inhibitors

Aaron B Keeley; Aleksandra Kopranovic; Vincenzo Di Lorenzo; Péter Ábrányi-Balogh; Niklas Jänsch; Linh N Lai; László Petri; Zoltán Orgován; Daniel Pölöske; Anna Orlova; András György Németh; Charlotte Desczyk; Tímea Imre; Dávid Bajusz; Richard Moriggl; Franz-Josef Meyer-Almes; György M Keserü

doi:10.1021/acs.jmedchem.3c01779

You are here:

PHAIDRA
Detail o:4251

Open in new window

Title (eng)

Electrophilic MiniFrags Revealed Unprecedented Binding Sites for Covalent HDAC8 Inhibitors

Author

Aaron B Keeley

Aleksandra Kopranovic

Vincenzo Di Lorenzo

Péter Ábrányi-Balogh

Niklas Jänsch

Linh N Lai

László Petri

Zoltán Orgován

Daniel Pölöske

University of Veterinary Medicine Vienna

Anna Orlova

University of Veterinary Medicine Vienna

András György Németh

Charlotte Desczyk

Tímea Imre

Dávid Bajusz

Richard Moriggl

University of Veterinary Medicine Vienna

Franz-Josef Meyer-Almes

György M Keserü

Abstract (eng)

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.

Keywords (eng)

Histone DeacetylasesFrgament LibrariesHot-SpotsDiscoveryDesign

Type (eng)

journal article

Language

[eng]

Persistent identifier

https://phaidra.vetmeduni.ac.at/o:4251

DOI

10.1021/acs.jmedchem.3c01779

Is in series

Title (eng)