Signal Transducer and Activator of Transcription 3 (STAT3) is a latent cytoplasmic protein overexpressed in various cancer cell 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 μM). Computational studies were carried out to investigate its binding mode. Moreover, compound MD77 showed a significant anti-proliferative 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 / D. Masciocchi, S. Villa, F. Meneghetti, A. Pedretti, D. Barlocco, L. Legnani, L. Toma, B.M. Kwon, S. Nakano, A. Asai, A. Gelain. - In: MEDCHEMCOMM. - ISSN 2040-2503. - 3:5(2012), pp. 592-599.

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

S. Villa
Secondo
;
F. Meneghetti;A. Pedretti;D. Barlocco;A. Gelain
Ultimo
2012

Abstract

Signal Transducer and Activator of Transcription 3 (STAT3) is a latent cytoplasmic protein overexpressed in various cancer cell 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 μM). Computational studies were carried out to investigate its binding mode. Moreover, compound MD77 showed a significant anti-proliferative activity versus several tumor cell lines. On these bases, compound MD77 was selected as a lead for the future development of direct STAT3 inhibitors.
polarizable continuum model; constitutive activation; cancer cells; apoptosis; optimization; proteins; dynamics; density; target; growth
Settore CHIM/08 - Chimica Farmaceutica
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/200503
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