8-benzyl-4-oxo-8-azabicyclo[3.2.1]oct-2-ene-6,7-dicarboxylic acid (SD-1008), a novel janus kinase 2 inhibitor, increases chemotherapy sensitivity in human ovarian cancer cells.
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 is a potential target for the new anticancer therapy. STAT3 is a DNA binding transcription factor, and therefore, its function depends on nuclear translocation. To discover inhibitors of the STAT3 pathway, we designed a cell-based screening assay capable of identifying small molecules that inhibit nuclear translocation. Among the 2000-compound National Cancer Institute Diversity set, we identified 8-benzyl-4-oxo-8-azabicyclo[3.2.1]oct-2-ene-6,7-dicarboxylic acid (SD-1008) as a micromolar inhibitor of interleukin-6 or oncostatin-induced STAT3 nuclear translocation. In addition, SD-1008 inhibits tyrosyl phosphorylation of STAT3, Janus kinase 2 (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-X(L) and survivin, inducing apoptosis. SD-1008 also enhances apoptosis induced by paclitaxel in ovarian cancer cells. These results demonstrate 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.
Department of Hematology/Oncology, Massachusetts General Hospital, 100 Blossom St. Jackson 1008, Boston, MA 02114, USA. zduan@partners.org
Zhenfeng
Z
Duan
James
J
Bradner
Edward
E
Greenberg
Ralph
R
Mazitschek
Rosemary
R
Foster
Jennifer
J
Mahoney
Michael V
MV
Seiden
D021581:Active Transport, Cell Nucleus; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors*; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D017239:Paclitaxel / Q000494:pharmacology; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014326:Tropanes / Q000627:therapeutic use*
C524881:8-benzyl-4-oxo-8-azabicyclo(3.2.1)oct-2-ene-6,7-dicarboxylic acid; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D047428:Protein Kinase Inhibitors; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D014326:Tropanes; D053614:Janus Kinase 2; D017239:Paclitaxel