Sorafenib derivatives induce apoptosis through inhibition of STAT3 independent of Raf
Journal
European Journal of Medicinal Chemistry
Journal Volume
46
Journal Issue
7
Pages
2845-2851
Date Issued
2011
Author(s)
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. ? 2011 Elsevier Masson SAS. All rights reserved.
SDGs
Other Subjects
1 [4 chloro 3 (trifluoromethyl)phenyl] 3 [4 (4 cyanophenoxy)phenyl]urea; 2 bromo n [4 (8 nitroquinolin 4 yloxy)phenyl) 4 (trifluoromethyl)benzenesulfonamide; 2 bromo n [4 (quinolin 4 yloxy)phenyl) 4 (trifluoromethyl)benzenesulfonamide; 2 fluoro n [4 (8 nitroquinolin 4 yloxy)phenyl] 5 (trifluoromethyl)benzamide; 2 fluoro n [4 (quinolin 4 yloxy)phenyl] 5 (trifluoromethyl)benzamide; 2 nitro n [4 (8 nitroquinolin 4 yloxy)phenyl] 4 (trifluorotrifluoromethyl)benzenesulfonamide; 2 nitro n [4 (quinolin 4 yloxy)phenyl] 4 (trifluoromethyl)benzenesulfonamide; 4 [4 (4 fluorophenylsulfonamido)phenoxy] n methylpicolinamide; 4 [4 (4 tert butylphenylsulfonamido)phenoxy] n methylpicolinamide; 4 [4 [2 bromo (4 trifluoromethyl)phenylsulfonamido]phenoxy] n methylpicolinamide; 4 [4 [3,5 bis(trifluoromethyl)benzamido]phenoxy] n methylpicolinamide; 4 [4 [5 fluoro 2(trifluoromethyl)benzamido]phenoxy] n methylpicolinamide; amide; n methyl 4 [4 (2 nitrophenylsulfonamido)phenoxy]picolinamide; n methyl 4 [4 (4 nitrophenylsulfonamido)phenoxy]picolinamide; n methyl 4 [4 (naphthalene 2 sulfonamido)phenoxy]picolinamide; n methyl 4 [4 (phenylsulfonamido)phenoxy]picolinamide; n methyl 4 [4 [4 (trifluoromethyl)benzamido]phenoxy]picolinamide; n [2 methyl 4 (8 nitroquinolin 4 yloxy)phenyl] 3,5 bis(trifluoromethyl)benzamide; n [4 (8 acetamidoquinolin 4 yloxy) 2 methylphenyl] 3,5 bis(trifluoromethyl)benzamide; n [4 (8 aminoquinolin 4 yloxy) 2-methylphenyl] 3,5 bis(trifluoromethyl)benzamide; n [4 (8 nitroquinolin 4 yloxy)phenyl] 3,5 bis(trifluoromethyl)benzamide; n [4 (quinolin 4 yloxy)phenyl) 3,5 bis(trifluoromethyl)benzamide; pyridine; Raf protein; sorafenib; STAT3 protein; sulfonamide; unclassified drug; unindexed drug; urea; amide; antineoplastic agent; carbanilamide derivative; nicotinamide; protein kinase inhibitor; Raf protein; sorafenib; STAT3 protein; STAT3 protein, human; sulfonamide; urea; apoptosis; article; drug design; drug mechanism; enzyme activation; protein function; signal transduction; structure activity relation; analogs and derivatives; antagonists and inhibitors; cell proliferation; chemistry; drug effects; drug screening; gene expression regulation; genetics; human; metabolism; phosphorylation; synthesis; tumor cell line; Amides; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Drug Screening Assays, Antitumor; Gene Expression Regulation, Neoplastic; Humans; Niacinamide; Phenylurea Compounds; Phosphorylation; Protein Kinase Inhibitors; raf Kinases; Signal Transduction; STAT3 Transcription Factor; Structure-Activity Relationship; Sulfonamides; Urea
Publisher
Elsevier Masson SAS
Type
journal article