Abstract
Signal transduction and activator of transcription (STAT) proteins are extracellular ligand-responsive transcription factors that mediate cell proliferation, apoptosis, differentiation, development and the immune response. Aberrant signals of STAT induce uncontrolled cell proliferation and apoptosis resistance and are strongly involved in cancer. STAT has been identified as a promising target for antitumor drugs, but to date most trials have not been successful. Here, we demonstrated that a novel STAT inhibitor, OPB-31121, strongly inhibited STAT3 and STAT5 phosphorylation without upstream kinase inhibition, and induced significant growth inhibition in various hematopoietic malignant cells. Investigation of various cell lines suggested that OPB-31121 is particularly effective against multiple myeloma, Burkitt lymphoma and leukemia harboring BCR–ABL, FLT3/ITD and JAK2 V617F, oncokinases with their oncogenicities dependent on STAT3/5. Using an immunodeficient mouse transplantation system, we showed the significant antitumor effect of OPB-31121 against primary human leukemia cells harboring these aberrant kinases and its safety for normal human cord blood cells. Finally, we demonstrated a model to overcome drug resistance to upstream kinase inhibitors with a STAT inhibitor. These results suggested that OPB-31121 is a promising antitumor drug. Phase I trials have been performed in Korea and Hong Kong, and a phase I/II trial is underway in Japan.
Highlights
Signal transduction and activator of transcription (STAT) proteins are extracellular ligand-responsive transcription factors that mediate a wide range of biological processes such as cell proliferation, apoptosis, differentiation, development and the immune response.[1,2] Stimulation with cytokines or growth factors results in the tyrosine phosphorylation of STAT proteins via the activation of upstream tyrosine kinases such as JAK family kinases (JFKs) and Src family kinases (SFKs).[3]
OPB-31121 selectively inhibits STAT phosphorylation without upstream kinase inhibition sensitive and insensitive cell lines. Sensitivity to this compound was independent of the strength of STAT3/5 phosphorylation detected by immunoblotting; looking at gene aberrations, leukemia cells harboring gene aberrations
Ltd. as a such as BCR–ABL, FLT3/ITD and JAK2 V617F were all sensitive to chemical that induced strong growth inhibition of various kinds of this compound (Table 2)
Summary
Signal transduction and activator of transcription (STAT) proteins are extracellular ligand-responsive transcription factors that mediate a wide range of biological processes such as cell proliferation, apoptosis, differentiation, development and the immune response.[1,2] Stimulation with cytokines or growth factors results in the tyrosine phosphorylation of STAT proteins via the activation of upstream tyrosine kinases such as JAK family kinases (JFKs) and Src family kinases (SFKs).[3]. Considering the strong association of STAT signaling with cancer development and the observed constitutive activation of STAT3/5 in various cancers, STAT3/5 have been identified as promising targets for antitumor drugs; to date most trials to block STAT signaling have not been fully successful.[22] Many trials aimed to inhibit upstream kinases such as JAK2; specific JAK2 inhibition was overcome by alternative activation of other JFKs.[23] Several JFK inhibitors are under development, but no significant clinical effect has been achieved. OPB-31121 did not inhibit activities of kinases including JFKs and SFKs and its exact mechanism of action is under investigation; it induced significant growth inhibition in a wide range of hematopoietic malignant cells. We demonstrated a model to overcome drug resistance to upstream kinase inhibitors with a STAT inhibitor. These results suggested that OPB-31121 is a promising antitumor drug. Phase I trials have been performed in Korea (NCT00955812) and Hong Kong (NCT00511082), and a phase I/II trial is underway in Japan (NCT1406574)
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