Combining computational modeling, de novo compound synthesis, and in vitro and cellular assays, we have performed an inhibition study against the enhancer of zeste homolog 2 (EZH2) histone-lysine N-methyltransferase. This enzyme is an important catalytic component of the PRC2 complex whose alterations have been associated with different cancers. We introduce here several tambjamine-inspired derivatives with low micromolar in vitro activity that produce a significant decrease in histone 3 trimethylation levels in cancer cells. We demonstrate binding at the methyl transfer active site, showing, in addition, that the EZH2 isolated crystal structure is capable of being used in molecular screening studies. Altogether, this work provides a successful molecular model that will help in the identification of new specific EZH2 inhibitors and identify a novel class of tambjamine-derived EZH2 inhibitors with promising activities for their use in cancer treatment.

This work was supported by grants from the Spanish Government (CTQ2016-79138-R; FIS PI13/00089), the Consejeria de Educacion de la Junta de Castilla y Leon (Projects BU340U13 and BU092U16), and from La Marato de TV3 Foundation (20132730). E.H. thanks the Junta de Castilla y Leon (Consejeria de Educacion) and Fondo Social Europeo for a PIRTU contract. OIDD screening data was supplied courtesy of Eli Lilly and Company- used with Lilly’s permission. To learn more about the Lilly Open Innovation Drug Discovery program, please visit the program Web site at https://openinnovation.lilly.com. Anti-trimethyl-Histone H3 (Lys27) antibody was a kind gift from Dr. Marian Martinez-Balbas (IBMB-CSIC), who helped us with technical assistance. We thank Dr. Benjamin Torrejon from CCiTUB (Centres CientifIcs i Tecnologics Universitat de Barcelona, Barcelona, Spain) for technical assistance.

Peer Reviewed