Sorafenib derivatives induce apoptosis through inhibition of STAT3 independent of Raf

作者：Chen Kuen Feng; Tai Wei Tien; Huang Jui Wen; Hsu Cheng Yi; Chen Wei Lin; Cheng Ann Lii; Chen Pei Jer; Shiau Chung Wai^*

来源：European Journal of Medicinal Chemistry, 2011, 46(7): 2845-2851.

DOI：10.1016/j.ejmech.2011.04.007

• Sorafenib
• STAT3
• Apoptosis

STAT3 is a transcription factor that modulates survival-directed transcription. It is persistently activated in many human cancers. Literature has shown that sorafenib, Raf kinase inhibitor, reduces Phospho-STAT3 and induces cell death. A series of sorafenib derivatives were synthesized as new inhibitors for STAT3. Urea, sulfonamide, and carboxamide linkers brought out different SARs from the end of sorafenib. Urea and carboxamide linked derivatives showed greater inhibition against STAT3 activity than sulfonamide linked derivatives. In particular, 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(4-cyanophenoxy) phenyl)urea (1), a urea linker, was as potent as sorafenib in reducing P-STAT3 level and cell death but no inhibition for Raf activity. Such result provides a new lead for the design of STAT3 inhibitors.

• 出版日期2011-7