Sorafenib derivatives induce apoptosis through inhibition of STAT3 independent of Raf

详细信息    查看全文

• 作者：Kuen-Feng Chen ; Wei-Tien Tai ; Jui-Wen Huang ; Cheng-Yi Hsu ; Wei-Lin Chen ; Ann-Lii Cheng ; Pei-Jer Chen ; Chung-Wai Shiau
• 关键词：Sorafenib ; STAT3 ; Apoptosis
• 刊名：European Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：July 2011
• 年：2011
• 卷：46
• 期：7
• 页码：2845-2851
• 全文大小：545 K

文摘

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.