Detalle Publicación

Discovery of reversible DNA methyltransferase and lysine methyltransferase G9a inhibitors with antitumoral in vivo efficacy

Autores: Rabal Gracia, María Obdulia; San José Enériz, Edurne; Aguirre Ena, Xabier; Sánchez Arias, Juan Antonio; Vilas Zornoza, Amaia; Ugarte, Ana; de Miguel, Irene; Miranda, Estíbaliz; Garate, Leire; Fraga, Mario; Santamarina, Pablo; Fernández Pérez, Raul; Ordóñez Ciriza, Raquel; Sáez de Blas, Elena; Roa Gómez, Sergio; García Barchino, María José; Martínez Climent, José Ángel; Liu, Yingying; Wu, Wei; Xu, Musheng; Prosper Cardoso, Felipe; Oyarzabal Santamarina, Julen
ISSN: 0022-2623
Volumen: 61
Número: 15
Páginas: 6518-6545
Fecha de publicación: 2018
Using knowledge- and structure-based approaches, we designed and synthesized reversible chemical probes that simultaneously inhibit the activity of two epigenetic targets, histone 3 lysine 9 methyltransferase (G9a) and DNA methyltransferases (DNMT), at nanomolar ranges. Enzymatic competition assays confirmed our design strategy: substrate competitive inhibitors. Next, an initial exploration around our hit 11 was pursued to identify an adequate tool compound for in vivo testing. In vitro treatment of different hematological neoplasia cell lines led to the identification of molecules with clear antiproliferative efficacies (GI50 values in the nanomolar range). On the basis of epigenetic functional cellular responses (levels of lysine 9 methylation and 5-methylcytosine), an acceptable therapeutic window (around 1 log unit) and a suitable pharmacokinetic profile, 12 was selected for in vivo proof-of-concept ( Nat. Commun. 2017 , 8 , 15424 ). Herein, 12 achieved a significant in vivo efficacy: 70% overall tumor growth inhibition of a human acute myeloid leukemia (AML) xenograft in a mouse model.