Identification of Eukaryotic Translation Elongation Factor 1-α 1 Gamendazole-Binding Site for Binding of 3-Hydroxy-4(1 H)-quinolinones as Novel Ligands with Anticancer Activity

0496892 - ÚEM 2019 RIV US eng J - Journal Article
Burglová, K. - Rylová, G. - Markoš, A. - Přichystalová, H. - Soural, M. - Petrácek, M. - Medvědiková, M. - Tejral, Gracian - Sopko, Bruno - Hradil, P. - Džubák, P. - Hajduch, M. - Hlaváč, J.
Identification of Eukaryotic Translation Elongation Factor 1-α 1 Gamendazole-Binding Site for Binding of 3-Hydroxy-4(1 H)-quinolinones as Novel Ligands with Anticancer Activity.
Journal of Medicinal Chemistry. Roč. 61, č. 7 (2018), s. 3027-3036. ISSN 0022-2623. E-ISSN 1520-4804
R&D Projects: GA MŠMT(CZ) LO1309; GA MŠMT(CZ) LO1508; GA ČR(CZ) GA15-15697S
Institutional support: RVO:68378041
Keywords : factor eef1a2 * nucleotide exchange * ternary complex * transfer-rna
OECD category: Biochemistry and molecular biology
Impact factor: 6.054, year: 2018

Here, we have identified the interaction site of the contraceptive drug gamendazole using computational modeling. The drug was previously described as a ligand for eukaryotic translation elongation factor 1-alpha 1 eEF1A1 and found to be a potential target site for derivatives of 2-phenyl-3-hydroxy-4 1H - quinolinones 3-HQs, which exhibit anticancer activity. The interaction of this class of derivatives of 3-HQs with eEF1A1 inside cancer cells was confirmed via pull-down assay. We designed and synthesized a new family of 3-HQs and subsequently applied isothermal titration calorimetry to show that these compounds strongly bind to eEF1A1. Further, we found that some of these derivatives possess significant in vitro anticancer activity.
Permanent Link: http://hdl.handle.net/11104/0294003