Small molecule inhibitors of Stat3 signaling pathway

被引:116
作者
Deng, Jinxia [1 ]
Grande, Fedora [1 ]
Neamati, Nouri [1 ]
机构
[1] Univ So Calif, Sch Pharm, Dept Pharmacol & Pharmaceut Sci, Los Angeles, CA 90089 USA
关键词
Stat3; inhibitors; apoptosis; Jak/Stat3; cancer therapy; Stats; signaling pathway;
D O I
10.2174/156800907780006922
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Constitutive activation of the Signal Transducers and Activators of Transcription 3 (Stat3) meditated signaling pathway is very important for cell growth and survival. Compelling evidence from mechanistic studies with antisense, RNA interference (RNAi), peptides, and small molecular inhibitors indicate that blocking Stat3 signaling can lead to successful suppression of tumor cell growth and apoptosis. Thus, Stat3 is an attractive molecular target for the development of novel cancer therapeutics. In this article, we present the first comprehensive review focusing on small molecule inhibitors that effectively block the Stat3 signaling pathway. These inhibitors, from a structural point of view, are divided into five classes of compounds. They include (1) natural products and derivatives, such as curcumin, resveratrol and others, (2) tyrphostins, (3) platinum-containing complexes, (4) peptidomimetics, and (5) azaspiranes. Some compounds may have multiple targets including Stat3 protein, therefore these compounds need further optimization and validation. The purpose of this review is to provide a resource for researchers interested in Stat3 targeted small molecules which will be beneficial for database development and template design for future drug development.
引用
收藏
页码:91 / 107
页数:17
相关论文
共 170 条
[71]   Flavopiridol disrupts STAT3/DNA interactions, attenuates STAT3-directed transcription, and combines with the Jak kinase inhibitor AG490 to achieve cytotoxic synergy [J].
Lee, YK ;
Isham, CR ;
Kaufman, SH ;
Bible, KC .
MOLECULAR CANCER THERAPEUTICS, 2006, 5 (01) :138-148
[72]   Targeted inhibition of Stat3 with a decoy oligonucleotide abrogates head and neck cancer cell growth [J].
Leong, PL ;
Andrews, GA ;
Johnson, DE ;
Dyer, KF ;
Xi, SC ;
Mai, JC ;
Robbins, PD ;
Gadiparthi, S ;
Burke, NA ;
Watkins, SF ;
Grandis, JR .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2003, 100 (07) :4138-4143
[73]   Bacterial N-acylhomoserine lactone-induced apoptosis in breast carcinoma cells correlated with down-modulation of STAT3 [J].
Li, L ;
Hooi, D ;
Chhabra, SR ;
Pritchard, D ;
Shaw, PE .
ONCOGENE, 2004, 23 (28) :4894-4902
[74]   THE ROLE OF SHARED RECEPTOR MOTIFS AND COMMON STAT PROTEINS IN THE GENERATION OF CYTOKINE PLEIOTROPY AND REDUNDANCY BY IL-2, IL-4, IL-7, IL-13, AND IL-15 [J].
LIN, JX ;
MIGONE, TS ;
TSANG, M ;
FRIEDMANN, M ;
WEATHERBEE, JA ;
ZHOU, L ;
YAMAUCHI, A ;
BLOOM, ET ;
MIETZ, J ;
JOHN, S ;
LEONARD, WJ .
IMMUNITY, 1995, 2 (04) :331-339
[75]   Antitumor agents. 250. Design and synthesis of new curcumin analogues as potential anti-prostate cancer agents [J].
Lin, Li ;
Shi, Qian ;
Nyarko, Alexander K. ;
Bastow, Kenneth F. ;
Wu, Chin-Chung ;
Su, Ching-Yuan ;
Shih, Charles C. -Y. ;
Lee, Kuo-Hsiung .
JOURNAL OF MEDICINAL CHEMISTRY, 2006, 49 (13) :3963-3972
[76]   Inhibition of vascular endothelial growth factor-induced angiogenesis by resveratrol through interruption of Src-dependent vascular endothelial cadherin tyrosine phosphorylation [J].
Lin, MT ;
Yen, ML ;
Lin, CY ;
Kuo, ML .
MOLECULAR PHARMACOLOGY, 2003, 64 (05) :1029-1036
[77]   Constitutive activation of JAK3/STAT3 in colon carcinoma tumors and cell lines - Inhibition of JAK3/STAT3 signaling induces apoptosis and cell cycle arrest of colon carcinoma cells [J].
Lin, Q ;
Lai, R ;
Chirieac, LR ;
Li, CP ;
Thomazy, VA ;
Grammatikakis, L ;
Rassidakis, GZ ;
Zhang, W ;
Fujio, Y ;
Kunisada, K ;
Hamilton, SR ;
Amin, HM .
AMERICAN JOURNAL OF PATHOLOGY, 2005, 167 (04) :969-980
[78]   Stat5a is mandatory for adult mammary gland development and lactogenesis [J].
Liu, XW ;
Robinson, GW ;
Wagner, KU ;
Garrett, L ;
WynshawBoris, A ;
Hennighausen, L .
GENES & DEVELOPMENT, 1997, 11 (02) :179-186
[79]   Role of the p38 MAPK pathway in cisplatin-based therapy [J].
Losa, JH ;
Cobo, CP ;
Viniegra, JG ;
Lobo, VJSA ;
Cajal, SRY ;
Sánchez-Prieto, R .
ONCOGENE, 2003, 22 (26) :3998-4006
[80]   Sustained activation of JNK/p38 MAPK pathways in response to cisplatin leads to Fas ligand induction and cell death in ovarian carcinoma cells [J].
Mansouri, A ;
Ridgway, LD ;
Korapati, AL ;
Zhang, QX ;
Tian, L ;
Wang, YB ;
Siddik, ZH ;
Mills, GB ;
Claret, FX .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2003, 278 (21) :19245-19256