2. Academic Validation
  3. First-in-Class Selective Inhibitors of the Lysine Acetyltransferase KAT8

First-in-Class Selective Inhibitors of the Lysine Acetyltransferase KAT8

  • J Med Chem. 2023 May 25;66(10):6591-6616. doi: 10.1021/acs.jmedchem.2c01937.
Francesco Fiorentino 1,  Sara Sementilli 2,  Martina Menna 1,  Federica Turrisi 2,  Stefano Tomassi 3,  Francesca Romana Pellegrini 2,  Angela Iuzzolino 2,  Francesca D'Acunzo 4,  Alessandra Feoli 5,  Hannah Wapenaar 6,  Sophie Taraglio 7,  Caterina Fraschetti 1,  Donatella Del Bufalo 8,  Gianluca Sbardella 5,  Frank J Dekker 6,  Alessandro Paiardini 7,  Daniela Trisciuoglio 2,  Antonello Mai 1 9,  Dante Rotili 1
Affiliations

Affiliations

  • 1 Department of Drug Chemistry and Technologies, Sapienza University of Rome, P.le A. Moro 5, Rome 00185, Italy.
  • 2 Institute of Molecular Biology and Pathology, National Research Council (CNR), Via degli Apuli 4, Rome 00185, Italy.
  • 3 Department of Pharmacy, University of Naples "Federico II", via Domenico Montesano 49, Naples 80131, Italy.
  • 4 Institute of Biological Systems (ISB), Italian National Research Council (CNR), Sezione Meccanismi di Reazione, c/o Department of Chemistry, Sapienza University of Rome, P. le A. Moro 5, Rome 00185, Italy.
  • 5 Department of Pharmacy, University of Salerno, via Giovanni Paolo II 132, Fisciano (SA) 84084, Italy.
  • 6 Department of Chemical and Pharmaceutical Biology, University of Groningen, Antonius Deusinglaan 1, Groningen 9713 AV, The Netherlands.
  • 7 Department of Biochemical Sciences, Sapienza University of Rome, P.le A. Moro 5, Rome 00185, Italy.
  • 8 Preclinical Models and New Therapeutic Agents Unit, IRCCS-Regina Elena National Cancer Institute, Via Elio Chianesi 53, Rome 00144, Italy.
  • 9 Pasteur Institute, Cenci-Bolognetti Foundation, Sapienza University of Rome, P.le A. Moro 5, Rome 00185, Italy.
PMID: 37155735 DOI: 10.1021/acs.jmedchem.2c01937
Abstract

KAT8 is a lysine acetyltransferase primarily catalyzing the acetylation of Lys16 of histone H4 (H4K16). KAT8 dysregulation is linked to the development and metastatization of many Cancer types, including non-small cell lung Cancer (NSCLC) and acute myeloid leukemia (AML). Few KAT8 inhibitors have been reported so far, none of which displaying selective activity. Based on the KAT3B/KDAC inhibitor C646, we developed a series of N-phenyl-5-pyrazolone derivatives and identified compounds 19 and 34 as low-micromolar KAT8 inhibitors selective over a panel of KATs and KDACs. Western blot, immunofluorescence, and CETSA experiments demonstrated that both inhibitors selectively target KAT8 in cells. Moreover, 19 and 34 exhibited mid-micromolar antiproliferative activity in different Cancer cell lines, including NSCLC and AML, without impacting the viability of nontransformed cells. Overall, these compounds are valuable tools for elucidating KAT8 biology, and their simple structures make them promising candidates for future optimization studies.

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