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Title: Inhibition of human enhancer of zeste homolog 2 with tambjamine analogs
Author: Kotev, Martin
Manuel-Manresa, Pilar
Hernando, Elsa
Soto Cerrato, Vanessa
Orozco López, Modesto
Quesada, Roberto
Pérez Tomás, Ricardo E.
Guallar, Victor
Keywords: Inhibició
Tractament adjuvant del càncer
Human beings
Adjuvant treatment of cancer
Issue Date: 1-Jan-2018
Publisher: American Chemical Society
Abstract: 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.
Note: Versió postprint del document publicat a:
It is part of: Journal of Chemical Information and Modeling, 2018, vol. 57, num. 8, p. 2089-2098
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ISSN: 1549-9596
Appears in Collections:Articles publicats en revistes (Patologia i Terapèutica Experimental)
Articles publicats en revistes (Institut de Recerca Biomèdica (IRB Barcelona))
Articles publicats en revistes (Bioquímica i Biomedicina Molecular)

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