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.

First-in-class selective inhibitors of the lysine acetyltransferase KAT8 / Fiorentino, Francesco; Sementilli, Sara; Menna, Martina; Turrisi, Federica; Tomassi, Stefano; Pellegrini, FRANCESCA ROMANA; Iuzzolino, Angela; D'Acunzo, Francesca; Feoli, Alessandra; Wapenaar, Hannah; Taraglio, Sophie; Fraschetti, Caterina; Del Bufalo, Donatella; Sbardella, Gianluca; Dekker, Frank J.; Paiardini, Alessandro; Trisciuoglio, Daniela; Mai, Antonello; Rotili, Dante. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 1520-4804. - 66:10(2023), pp. 6591-6616. [10.1021/acs.jmedchem.2c01937]

First-in-class selective inhibitors of the lysine acetyltransferase KAT8

Francesco Fiorentino;Sara Sementilli;Martina Menna;Federica Turrisi;Stefano Tomassi;Francesca Romana Pellegrini;Angela Iuzzolino;Francesca D’Acunzo;Sophie Taraglio;Caterina Fraschetti;Alessandro Paiardini;Daniela Trisciuoglio
;
Antonello Mai
;
Dante Rotili
2023

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.
2023
lysine acetyltransferas; n-phenyl-5-pyrazolone derivatives; kat8
01 Pubblicazione su rivista::01a Articolo in rivista
First-in-class selective inhibitors of the lysine acetyltransferase KAT8 / Fiorentino, Francesco; Sementilli, Sara; Menna, Martina; Turrisi, Federica; Tomassi, Stefano; Pellegrini, FRANCESCA ROMANA; Iuzzolino, Angela; D'Acunzo, Francesca; Feoli, Alessandra; Wapenaar, Hannah; Taraglio, Sophie; Fraschetti, Caterina; Del Bufalo, Donatella; Sbardella, Gianluca; Dekker, Frank J.; Paiardini, Alessandro; Trisciuoglio, Daniela; Mai, Antonello; Rotili, Dante. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 1520-4804. - 66:10(2023), pp. 6591-6616. [10.1021/acs.jmedchem.2c01937]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1681512
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