Discovery of a Novel Chemotype of Histone Lysine Methyltransferase EHMT1/2 (GLP/G9a) Inhibitors: Rational Design, Synthesis, Biological Evaluation, and Co-crystal Structure

Milite, Ciro; Feoli, Alessandra; Horton, John R.; Rescigno, Donatella; Cipriano, Alessandra; Pisapia, Vincenzo; Viviano, Monica; Pepe, Giacomo; Amendola, Giorgio; Novellino, Ettore; Cosconati, Sandro; Cheng, Xiaodong; Castellano, Sabrina; Sbardella, Gianluca

doi:10.1021/acs.jmedchem.8b02008

Discovery of a Novel Chemotype of Histone Lysine Methyltransferase EHMT1/2 (GLP/G9a) Inhibitors: Rational Design, Synthesis, Biological Evaluation, and Co-crystal Structure

Journal Article · Tue Feb 12 00:00:00 EST 2019 · Journal of Medicinal Chemistry

DOI:https://doi.org/10.1021/acs.jmedchem.8b02008· OSTI ID:1506510

^[1]; Feoli, Alessandra ^[1]; Horton, John R. ^[2]; Rescigno, Donatella ^[1]; Cipriano, Alessandra ^[1]; Pisapia, Vincenzo ^[1]; Viviano, Monica ^[1]; Pepe, Giacomo ^[1]; ^[3]; ^[4]; ^[3]; Cheng, Xiaodong ^[2]; Castellano, Sabrina ^[1]; ^[1]

Univ. of Salerno, Fisciano, SA (Italy)
The Univ. of Texas MD Anderson Cancer Center, Houston, TX (United States)
Univ. of Campania “Luigi Vanvitelli”, Caserta (Italy). DiSTABiF
Univ. Federico II of Naples (Italy)

Since the discovery of compound BIX01294 over 10 years ago, only a very limited number of nonquinazoline inhibitors of H3K9-specific methyltransferases G9a and G9a-like protein (GLP) have been reported. In this paper, we report the identification of a novel chemotype for G9a/GLP inhibitors, based on the underinvestigated 2-alkyl-5-aminoand 2-aryl-5-amino-substituted 3$$H$$-benzo[$$e$$][1,4]diazepine scaffold. Our research efforts resulted in the identification 12a (EML741), which not only maintained the high in vitro and cellular potency of its quinazoline counterpart, but also displayed improved inhibitory potency against DNA methyltransferase 1, improved selectivity against other methyltransferases, low cell toxicity, and improved apparent permeability values in both parallel artificial membrane permeability assay (PAMPA) and blood–brain barrier-specific PAMPA, and therefore might potentially be a better candidate for animal studies. Finally, the co-crystal structure of GLP in complex with 12a provides the basis for the further development of benzodiazepine-based G9a/GLP inhibitors.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: Cancer Prevention and Research Institute of Texas (CPRIT); European Cooperation in Science and Technology (COST); Italian Ministero dell’Istruzione, dell’Universitàe della Ricerca (MIUR), Progetti di Ricerca di Interesse Nazionale; National Institutes of Health (NIH); Università di Salerno

OSTI ID:: 1506510

Journal Information:: Journal of Medicinal Chemistry, Journal Name: Journal of Medicinal Chemistry Journal Issue: 5 Vol. 62; ISSN 0022-2623

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Two novel SIRT1 activators, SCIC2 and SCIC2.1, enhance SIRT1-mediated effects in stress response and senescence Scisciola, Lucia; Sarno, Federica; Carafa, Vincenzo Epigenetics, Vol. 15, Issue 6-7 https://doi.org/10.1080/15592294.2019.1704349	journal	January 2020

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