Journal of Medicinal Chemistry p. 6518 - 6545 (2018)
Update date:2022-08-15
Topics:
Rabal, Obdulia
José-Enériz, Edurne San
Agirre, Xabier
Sánchez-Arias, Juan Antonio
Vilas-Zornoza, Amaia
Ugarte, Ana
De Miguel, Irene
Miranda, Estíbaliz
Garate, Leire
Fraga, Mario
Santamarina, Pablo
Perez, Raul Fernandez
Ordo?ez, Raquel
Sáez, Elena
Roa, Sergio
García-Barchino, María José
Martínez-Climent, José Angel
Liu, Yingying
Wu, Wei
Xu, Musheng
Prosper, Felipe
Oyarzabal, Julen
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.
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