MolPharm

Home Help [Feedback] [For Subscribers] [Archive] [Search] --
QUICK SEARCH:   [advanced]


     

Molecular Pharmacology Fast Forward
First published on August 3, 2007; DOI: 10.1124/mol.107.038117

This Article
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
mol.107.038117v1
72/5/1137    most recent
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Duan, Z.
Right arrow Articles by Seiden, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Duan, Z.
Right arrow Articles by Seiden, M.


Received for publication May 15, 2007.
Revised August 2, 2007.
Accepted for publication August 3, 2007.

SD-1008 a Novel JAK2 Inhibitor, Increases Chemotherapy Sensitivity in Human Ovarian Cancer Cells

Zhenfeng Duan 1*, James Bradner 2, Edward Greenberg 2, Ralph Mazitschek 2, Rosemary Foster 1, Jennifer Mahoney 1, Michael Seiden 1

1 Massachusetts General Hospital 2 Broad Institute of Harvard and MIT

* Address correspondence to: E-mail: zduan{at}partners.org

Abstract

Interleukin 6 and the Signal transducer and activator of transcription (STAT) 3 proteins have important roles in cancer cell survival and proliferation. Recent studies demonstrate that abnormal STAT3 activation promotes tumor growth and supports survival of many human cancers and thus this protein or the pathway responsible for its activation are potential targets for the new anti-cancer therapy. STAT3 is a DNA-binding transcription factor and therefore its function depends on nuclear translocation. To discover inhibitors of the STAT3 pathway we have designed a cell-based screening assay capable of identifying small molecules which inhibit nuclear translocation. Among the 2000-compound NCI Diversity set we have identified SD-1008 as a micromolar inhibitor of IL-6 or oncostatin-induced STAT3 nuclear translocation. Additionally, SD-1008 inhibits tyrosyl phosphorylation of STAT3, JAK2 and Src. SD-1008 also reduces STAT3-dependent luciferase activity. Biochemical studies with recombinant JAK2 proteins demonstrate that high concentrations of SD-1008 directly inhibit JAK2 kinase autophosphorylation. Exposure of various cell lines to SD-1008 decreases levels of the STAT3 dependent proteins, Bcl-XL and survivin, inducing apoptosis. SD-1008 also enhances apoptosis induced by paclitaxel in ovarian cancer cells. These results demonstrated that SD-1008 directly blocks the JAK-STAT3 signaling pathway in human cancer cells that express constitutively active Stat and add to the growing literature that identifies this pathway as a viable target for drug development. Finally, SD-1008 may be a suitable prototype for further chemical modification and exploration as a therapeutic agent.


Key words: Interleukins, Jak/Stats, Stat activated transcriptional events, Protein Kinases (other), Src and other nonreceptor tyrosine kinases, Mechanisms of cell killing/apoptosis, Resistance, Transcription targets


This article has been cited by other articles:


Home page
 Molecular Cancer TherapeuticsHome page
J. Sayyah, A. Magis, D. A. Ostrov, R. W. Allan, R. C. Braylan, and P. P. Sayeski
Z3, a novel Jak2 tyrosine kinase small-molecule inhibitor that suppresses Jak2-mediated pathologic cell growth
Mol. Cancer Ther., August 1, 2008; 7(8): 2308 - 2318.
[Abstract] [Full Text] [PDF]


Home Help [Feedback] [For Subscribers] [Archive] [Search] --
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 2007 by the American Society for Pharmacology and Experimental Therapeutics