2026-04-29T05:26:00Zhttps://riubu.ubu.es/oai/requestoai:riubu.ubu.es:10259/48812021-11-10T09:38:19Zcom_10259_3924com_10259_5086com_10259_2604col_10259_3925
Inhibition of human enhancer of zeste homolog 2 with tambjamine analogs
Kotev, Martin .
Manuel Manresa, Pilar .
Hernando Santa Cruz, Elsa
Soto Cerrato, Vanessa
Orozco, Modesto .
Quesada Pato, Roberto
Pérez Tomás, Ricardo
Guallar, Victor
Química orgánica
Chemistry, Organic
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.
Spanish
Government (CTQ2016-79138-R; FIS PI13/00089), the
Consejería
de Educación de la Junta de Castilla y León
(Projects BU340U13 and BU092U16), and from La Maratóde
TV3 Foundation (20132730).
2018-08-24T09:48:45Z
2018-08-24T09:48:45Z
2017-08
info:eu-repo/semantics/article
info:eu-repo/semantics/acceptedVersion
1549-9596
http://hdl.handle.net/10259/4881
10.1021/acs.jcim.7b00178
eng
Journal of Chemical Information and Modeling. 2017, V. 57, n. 8, p. 2089-2098
https://doi.org/10.1021/acs.jcim.7b00178
info:eu-repo/grantAgreement/MICINN/CTQ2016-79138-R
info:eu-repo/grantAgreement/MSCBS/PI13-00089
info:eu-repo/grantAgreement/JCyL/BU340U13
info:eu-repo/grantAgreement/JCyL/BU092U16
info:eu-repo/grantAgreement/TV3Foundation/20132730
info:eu-repo/semantics/openAccess
application/pdf
American Chemical Society