Histone deacetylases (HDAC) are enzymes that regulate the concentration of acetylated histones which, in turns, interact with the bromodomain (BRD) of BET (Bromodomain and Extracellular domain) proteins to affect transcriptional activity. Simultaneous blockade of both epigenetic players has shown synergistic effects in a variety of cancer cell lines. In this paper we report the design, synthesis and activity of new dual inhibitors, obtained by adding a methyltriazole moiety to some HDAC inhibitors carrying a benzodiazepine core, which were previously developed by us. An Alphascreen FRET assay showed that the compounds were able to interact with BRD4-1 and BRD4-2 proteins, with some selectivity for the latter, while the HDAC inhibiting properties were measured by means of an immunoprecipitation assay. The antiproliferative activity was tested on C26 adenocarcinoma, SSMC2 melanoma and SHSY5Y neuroblastoma cells. Interestingly, both compounds were endowed with antihyperalgesic activity in the mouse Spared Nerve Injury (SNI) model. [Figure not available: see fulltext.]

Dual HDAC–BRD4 inhibitors endowed with antitumor and antihyperalgesic activity / Maach S.; Chiaramonte N.; Borgonetti V.; Sarno F.; Pierucci F.; Dei S.; Teodori E.; Altucci L.; Meacci E.; Galeotti N.; Romanelli M.N.. - In: MEDICINAL CHEMISTRY RESEARCH. - ISSN 1054-2523. - STAMPA. - (2022), pp. 1-15. [10.1007/s00044-022-02896-w]

Dual HDAC–BRD4 inhibitors endowed with antitumor and antihyperalgesic activity

Maach S.;Chiaramonte N.;Borgonetti V.;Pierucci F.;Dei S.;Teodori E.;Meacci E.;Galeotti N.;Romanelli M. N.
2022

Abstract

Histone deacetylases (HDAC) are enzymes that regulate the concentration of acetylated histones which, in turns, interact with the bromodomain (BRD) of BET (Bromodomain and Extracellular domain) proteins to affect transcriptional activity. Simultaneous blockade of both epigenetic players has shown synergistic effects in a variety of cancer cell lines. In this paper we report the design, synthesis and activity of new dual inhibitors, obtained by adding a methyltriazole moiety to some HDAC inhibitors carrying a benzodiazepine core, which were previously developed by us. An Alphascreen FRET assay showed that the compounds were able to interact with BRD4-1 and BRD4-2 proteins, with some selectivity for the latter, while the HDAC inhibiting properties were measured by means of an immunoprecipitation assay. The antiproliferative activity was tested on C26 adenocarcinoma, SSMC2 melanoma and SHSY5Y neuroblastoma cells. Interestingly, both compounds were endowed with antihyperalgesic activity in the mouse Spared Nerve Injury (SNI) model. [Figure not available: see fulltext.]
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Maach S.; Chiaramonte N.; Borgonetti V.; Sarno F.; Pierucci F.; Dei S.; Teodori E.; Altucci L.; Meacci E.; Galeotti N.; Romanelli M.N.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2158/1269945
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