Sorafenib derivatives induce apoptosis through inhibition of STAT3 independent of Raf

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.

Graphical abstractSorafenib derivative was synthesized with two steps. It has no inhibition against Raf kinase and contains ability to reduce STAT3 activity. We generated a series of derivatives to test the their ability to reduce P-STAT3.Figure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Sorafenib and sorafenib derivative have the cytotoxicity against HCC. ► Both compounds have inhibition in STAT3. ► The derivative has no inhibition in Raf kinase, a target of sorafenib. ► A series of derivatives were synthesized with two steps and tested for STAT3 inhibition in HCC.