Histone lysine methyltransferases have crucial roles in a number of biological processes and human diseases by controlling gene expression and chromatin state. Within this family, the lysine methyltransferase G9a has emerged as a critical player in several pathologic states, mainly due to its important role in the silencing of tumour suppressor genes and in the regulation of other chromatin events (1). Despite the extensive research for new chemical entities, to date there is a low number of G9a chemical probes suitable for cell-based and animal studies, only bearing to the quinazoline class and among all the UNC0638 is the most used and best characterized compound (2). Keeping this in mind and pursuing our efforts toward the identification of potent and selective histone lysinemethyltransferases inhibitors, we replaced the quinazoline moiety of the UNC0638 with a benzodiazepine framework, obtaining the EML741. Herein we present the design and synthesis of the EML741 and its inhibitory activity toward G9a HMTase as well as its selectivity profile on other epigenetic enzymes. Moreover, we report the ability of EML741 to lower the G9a activity level in tumor cell lines.

Expanding the quinazoline ring to 3H-benzo[e][1,4]diazepine: development of new and selective G9a inhibitors

C. Milite;A. Feoli;RESCIGNO, DONATELLA;PISAPIA, VINCENZO;S. Castellano;G. Sbardella
2018-01-01

Abstract

Histone lysine methyltransferases have crucial roles in a number of biological processes and human diseases by controlling gene expression and chromatin state. Within this family, the lysine methyltransferase G9a has emerged as a critical player in several pathologic states, mainly due to its important role in the silencing of tumour suppressor genes and in the regulation of other chromatin events (1). Despite the extensive research for new chemical entities, to date there is a low number of G9a chemical probes suitable for cell-based and animal studies, only bearing to the quinazoline class and among all the UNC0638 is the most used and best characterized compound (2). Keeping this in mind and pursuing our efforts toward the identification of potent and selective histone lysinemethyltransferases inhibitors, we replaced the quinazoline moiety of the UNC0638 with a benzodiazepine framework, obtaining the EML741. Herein we present the design and synthesis of the EML741 and its inhibitory activity toward G9a HMTase as well as its selectivity profile on other epigenetic enzymes. Moreover, we report the ability of EML741 to lower the G9a activity level in tumor cell lines.
2018
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11386/4719176
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