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Synthesis and Structure–Activity Relationship Studies of Small Molecule Disruptors of EWS-FLI1 Interactions in Ewing’s Sarcoma

[Image: see text] EWS-FLI1 is an oncogenic fusion protein implicated in the development of Ewing’s sarcoma family tumors (ESFT). Using our previously reported lead compound 2 (YK-4-279), we designed and synthesized a focused library of analogues. The functional inhibition of the analogues was measur...

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Detalles Bibliográficos
Autores principales: Tosso, Perrer N., Kong, Yali, Scher, Lauren, Cummins, Ryan, Schneider, Jeffrey, Rahim, Said, Holman, K. Travis, Toretsky, Jeffrey, Wang, Kan, Üren, Aykut, Brown, Milton L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2014
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4281097/
https://www.ncbi.nlm.nih.gov/pubmed/25432018
http://dx.doi.org/10.1021/jm501372p
Descripción
Sumario:[Image: see text] EWS-FLI1 is an oncogenic fusion protein implicated in the development of Ewing’s sarcoma family tumors (ESFT). Using our previously reported lead compound 2 (YK-4-279), we designed and synthesized a focused library of analogues. The functional inhibition of the analogues was measured by an EWS-FLI1/NR0B1 reporter luciferase assay and a paired cell screening approach measuring effects on growth inhibition for human cells containing EWS-FLI1 (TC32 and TC71) and control PANC1 cell lines devoid of the oncoprotein. Our data revealed that substitution of electron donating groups at the para-position on the phenyl ring was the most favorable for inhibition of EWS-FLI1 by analogs of 2. Compound 9u (with a dimethylamino substitution) was the most active inhibitor with GI(50) = 0.26 ± 0.1 μM. Further, a correlation of growth inhibition (EWS-FLI1 expressing TC32 cells) and the luciferase reporter activity was established (R(2) = 0.84). Finally, we designed and synthesized a biotinylated analogue and determined the binding affinity for recombinant EWS-FLI1 (K(d) = 4.8 ± 2.6 μM).