Discovery of Reversible DNA Methyltransferase and Lysine Methyltransferase G9a Inhibitors with Antitumoral in Vivo Efficacy

作者：Rabal Obdulia; San Jose Eneriz Edurne; Agirre Xabier; Antonio Sanchez Arias Juan; Vilas Zornoza Amaia; Ugarte Ana; de Miguel Irene; Miranda Estibaliz; Garate Leire; Fraga Mario; Santamarina Pablo; Fernandez Perez Raul; Ordonez Raquel; Saez Elena; Roa Sergio; Jose Garcia Barchino Maria; Angel Martinez Climent Jose; Liu Yingying; Wu Wei; Xu Musheng; Prosper Felipe^*; Oyarzabal Julen^*

来源：Journal of Medicinal Chemistry, 2018, 61(15): 6518-6545.

DOI：10.1021/acs.jmedchem.7b01926

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 (GI(50) 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.

• 出版日期2018-8-9