|
In the last post, I have introduced the Pim kinases, the kinase inhibitor SGI-1776 and their action in the process and treatment of AML. And I will continue to talk about the Pim inhibitors and the corresponding mechanism in the regulation of JAK/STAT signaling pathway. As I have mentioned in my previous post, there are three members identified in Pim kinase family. Because of differences in the composition, some differences on function level also exist. The pim-1 proto-oncogene/serine/threonine-protein kinase is first deiscribed as a locus frequently activated by proviral integration in Moloney murine leukemia virus–induced mouse T-cell lymphomas. Pim-1 is mainly involved in cell cycle regulation, apoptosis and transcriptional activation. While Pim-2 is considered as a gene frequently activated in secondary transplants of virus-induced lymphomas, and has also been shown to confer rapamycin resistance in T lymphocytes. Pim-3 expression is enhanced in several cancer tissues, particularly those of endoderm-derived organs, including the liver, pancreas, colon, and stomach. Pim kinases can regulate cell proliferation, and the molecular mechanisms are demonstrated to include the blocking of cell cycle inhibitors p27Kip1 or p21cip1 or the activation of factors that promote cell cycle, such as CDC25A, CDC25C, or the kinase C-TAK1. And the regulation of Pim kinases on cell viability is acted by phosphorylating the apoptotic proteins BAD and ASK1. The JAK/STAT pathway is reported to be involved in the regulation of Pim expression and activity, and STAT3 is one of the transcription factors that regulates the transcription of Pims. SGI-1776, as a novel Pim inhibitor, has been demonstrated to inhibit the survival of leukemia cells and the proliferation of prostate cancer cell lines in the existing reports. In a recent paper, it is reported that Chang and the colleagues identified small chemical compounds that inhibit cell survival using a cell-based high throughput screening. Three agents, 21A8, 21H7, and 65D4 are selected at last, and 65D4 exhibits a promising anticancer activities on lymphoma cells as well as on cells derived from solid tumors. Then after some structural changes in 65D4, M-110 is established as a potent and selective PIM kinase inhibitor, and can inhibit all three members of the PIM kinase family but is most active on PIM-3. The use of selective PIM inhibitors and PIM isoform–specific knockdown experiments indicate that cells with M-110 significantly attenuates the induction of pSTAT3Tyr705 and expression of some downstream genes, suggesting that PIM-3 kinase is a positive regulator of STAT3 activation[1]. Taken together, M-110, as the novel Pim inhibitor, inhibits the expression of active STAT3 through inhibition of PIM-3. Since many patient tumors express activated STAT3, M-110 may represent the potential therapy for patients with related tumors. We has established long-term and stable relationships with more than 10,000 customers from pharmaceutical and biotech companies, universities and research institutions. We have high quality inhibitors like hdac inhibitor, hdac inhibitors, Taxol & more. We have headquarters in both United States and Europe, and also has 38 distributors worldwide. We provide overnight delivery in North America and Europe. References [1]. Mol Cancer Ther 2010;9:2478-2487. Related Post SGI-1776, the potential therapy against AML
Related Articles -
hdac inhibitor, hdac inhibitors, Taxol,
|
