1. Sorafenib derivatives induce apoptosis through inhibition of STAT3 independent of Raf.
- Author
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Chen KF, Tai WT, Huang JW, Hsu CY, Chen WL, Cheng AL, Chen PJ, and Shiau CW
- Subjects
- Amides chemistry, Antineoplastic Agents pharmacology, Apoptosis drug effects, Cell Line, Tumor, Cell Proliferation drug effects, Drug Screening Assays, Antitumor, Humans, Niacinamide chemistry, Niacinamide pharmacology, Phenylurea Compounds pharmacology, Phosphorylation, Protein Kinase Inhibitors pharmacology, STAT3 Transcription Factor antagonists & inhibitors, STAT3 Transcription Factor metabolism, Signal Transduction, Sorafenib, Structure-Activity Relationship, Sulfonamides chemistry, Urea chemistry, raf Kinases genetics, raf Kinases metabolism, Antineoplastic Agents chemical synthesis, Gene Expression Regulation, Neoplastic, Niacinamide analogs & derivatives, Phenylurea Compounds chemistry, Protein Kinase Inhibitors chemical synthesis, STAT3 Transcription Factor genetics
- Abstract
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., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)
- Published
- 2011
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