Signal Transducer and Activator of Transcription 3 (STAT3) is a latent cytoplasmic protein overexpressed in various cancer c ell lines. STAT3 participates in oncogenesis by stimulating cell proliferation and preventing apoptosis and it has been proven as a suitable target for anticancer therapy. In order to identify direct STAT3 inhibitors, we performed a binding assay on several previously synthesized 1,2,5-oxadiazole derivatives. Among them, compound MD77, N-[4-(4- chlorophenyl)-1,2,5-oxadiazol-3-yl]-4-(trifluoromethyl)benzamide, showed a good ability to bind the STAT3–SH2 domain in a dose-dependent manner (IC50 = 17.7 microM). Computational studies were carried out to investigate its binding mode. Moreover, compound MD77 showed a significant antiproliferative activity versus several tumor cell lines. On these bases, compound MD77 was selected as a lead for the future development of direct STAT3 inhibitors.

Biological and computational evaluation of an oxadiazole derivative (MD77) as a new lead for direct STAT3 inhibitors

LEGNANI, LAURA;TOMA, LUCIO;
2012

Abstract

Signal Transducer and Activator of Transcription 3 (STAT3) is a latent cytoplasmic protein overexpressed in various cancer c ell lines. STAT3 participates in oncogenesis by stimulating cell proliferation and preventing apoptosis and it has been proven as a suitable target for anticancer therapy. In order to identify direct STAT3 inhibitors, we performed a binding assay on several previously synthesized 1,2,5-oxadiazole derivatives. Among them, compound MD77, N-[4-(4- chlorophenyl)-1,2,5-oxadiazol-3-yl]-4-(trifluoromethyl)benzamide, showed a good ability to bind the STAT3–SH2 domain in a dose-dependent manner (IC50 = 17.7 microM). Computational studies were carried out to investigate its binding mode. Moreover, compound MD77 showed a significant antiproliferative activity versus several tumor cell lines. On these bases, compound MD77 was selected as a lead for the future development of direct STAT3 inhibitors.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11571/420733
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