Identification and in vitro characterization of a new series of potent and highly selective G9a inhibitors as novel anti-fibroadipogenic agents

Pietro Randazzo; Roberta Sinisi; Davide Gornati; Stefania Bertuolo; Leda Bencheva; Marilenia De Matteo; Martina Nibbio; Edith Monteagudo; Lorenzo Turcano; Valeria Bianconi; Giovanna Peruzzi; Vincenzo Summa; Alberto Bresciani; Chiara Mozzetta; Romano Di Fabio

doi:10.1016/j.bmcl.2022.128858

Identification and in vitro characterization of a new series of potent and highly selective G9a inhibitors as novel anti-fibroadipogenic agents

Bioorg Med Chem Lett. 2022 Sep 15:72:128858. doi: 10.1016/j.bmcl.2022.128858. Epub 2022 Jun 16.

Authors

Affiliations

¹ Promidis, Via Olgettina 60, 20132 Milano, Italy.
² IRBM Science Park, Via Pontina Km 30.600, 00070 Pomezia, Italy.
³ CHDI Foundation, 6080 Center Drive, Suite 700, CA 90045, Los Angeles.
⁴ Institute of Molecular Biology and Pathology (IBPM), National Research Council (CNR) of Italy c/o, Department of Biology and Biotechnology "C. Darwin", Sapienza University, Piazzale A. Moro 5, 00185 Rome, Italy.
⁵ Center for Life Nano- & Neuro-Science, Fondazione Istituto Italiano di Tecnologia (IIT), V.le Regina, Elena 291, 00161 Rome, Italy.
⁶ University of Naples Federico II, Vial Domenico Montesano 49, 80131, Naples, Italy.
⁷ Exscientia LTD, The Schrödinger Building Oxford Science Park, Oxford OX4 4GE, UK.
⁸ Promidis, Via Olgettina 60, 20132 Milano, Italy; IRBM Science Park, Via Pontina Km 30.600, 00070 Pomezia, Italy. Electronic address: r.difabio@irbm.com.

PMID: 35718104
DOI: 10.1016/j.bmcl.2022.128858

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.

Keywords: Duchenne muscle dystrophy; G9a; GLP; H3K9 methylation; Skeletal muscle regeneration.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Enzyme Inhibitors / pharmacology
Histone-Lysine N-Methyltransferase*
Histones*

Substances

Enzyme Inhibitors
Histones
Histone-Lysine N-Methyltransferase