Identification and in vitro characterization of a new series of potent and highly selective G9a inhibitors as novel anti-fibroadipogenic agents. (15th September 2022)

• Record Type: Journal Article
• Authors: Randazzo, Pietro; Sinisi, Roberta; Gornati, Davide; Bertuolo, Stefania; Bencheva, Leda; De Matteo, Marilenia; Nibbio, Martina; Monteagudo, Edith; Turcano, Lorenzo; Bianconi, Valeria; Peruzzi, Giovanna; Summa, Vincenzo; Bresciani, Alberto; Mozzetta, Chiara; Di Fabio, Romano
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 72(2022)
• Publication Date: 2022-09-15
• Subjects: H3K9 methylation -- G9a -- GLP -- Skeletal muscle regeneration -- Duchenne muscle dystrophy; PTM post-translational modifications -- HMT histone methyl transferases -- EHMT2 euchromatic histone N-methyltransferase 2 -- EHMT1 euchromatic histone-lysine N-methyltransferase 1 -- KMTs lysine methyltransferases -- SAM S-adenosyl-l-Met -- H3K9m1 mono-methylation of Lys 9 on histone H3 -- H3K9m2 di-methylation of Lys 9 on histone H3 -- MyHC+ Myosin Heavy Chain positive; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2022.128858
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: A new series of in vitro potent and highly selective histone methyl transferase enzyme G9a inhibitors was obtained. In particular, compound 2a, one the most potent G9a inhibitor identified, was endowed with >130-fold selectivity over GLP and excellent ligand efficiency. Therefore, it may represent a valuable tool compound to validate the role of highly selective G9a inhibitors in different pathological conditions. When 2a was characterized in vitro in cellular models of skeletal muscle differentiation, a relevant increase of myofibers' size and reduction of the fibroadipogenic infiltration were observed, further confirming the therapeutic potential of selective G9a inhibitors for the treatment of Duchenne muscle dystrophy.