作者
Obdulia Rabal, Edurne San Jose-Eneriz, Xabier Agirre, Juan Antonio Sánchez-Arias, Amaia Vilas-Zornoza, Ana Ugarte, Irene de Miguel, Estibaliz Miranda, Leire Garate, Mario Fraga, Pablo Santamarina, Raul Fernandez Perez, Raquel Ordonez, Elena Saez, Sergio Roa, María José García-Barchino, José Angel Martínez-Climent, Yingying Liu, Wei Wu, Musheng Xu, Felipe Prosper, Julen Oyarzabal
发表日期
2018/6/28
期刊
Journal of Medicinal Chemistry
卷号
61
期号
15
页码范围
6518-6545
出版商
American Chemical Society
简介
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 …
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O Rabal, E San Jose-Eneriz, X Agirre… - Journal of Medicinal Chemistry, 2018