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• W3046261291 abstract "2390 Janus kinase 2 (JAK2) is a cytokine receptor associated tyrosine kinase. Binding of cytokines to their specific receptors leads to their dimerization and activation of associated JAKs. Activated JAKs phosphorylate specific tyrosine residues in the cytoplasmic chains of the receptor, which now act as docking sites for SH2 containing latent transcription factors known as STATs. Once bound to the receptor, STATs are activated by JAKs through phosphorylation of their tyrosine residues. Activated STATs form stable dimers and translocate to the nucleus, where they bind specific promoter sequences of their target genes involved in cell proliferation and survival, such as Bcl-xL, Bcl-2, c-myc and cyclin D1. Tumor cell lines and samples derived from hematopoetic malignancies (leukemia, lymphoma and multiple myeloma) and solid tumors (breast, head and neck, lung, prostrate and ovarian cancers) exhibit deregulated JAK-STAT signaling, which can be attributed to autocrine cytokine production or growth factor stimulation by tumor cells or microenvironment. Tel-JAK2 mutants, caused by chromosomal translocations, are constitutively active and induce myeloid and lymphoid leukemias. Recent studies have also demonstrated an activating mutation in JAK2 (V617F) which underlies many myeloid disorders. Tryphostin AG490 is the most commonly studied kinase inhibitor of JAK2. Although AG490 inhibits tumor cell growth and increases sensitivity to apoptotic stimuli in vitro, in vivo studies have been less promising as AG490 has limited activity in animals and high concentrations (50-100 μM) are required to achieve significant anti-tumor effects. In a search for more effective inhibitors of JAK2, our research group screened over 300 analogs of AG490 for their ability to inhibit JAK2. Based in structure activity analysis, a small molecule inhibitor was designed and synthesized (WP1130), which inhibited JAK2 mediated STAT3 activation by inducing down regulation of JAK2 at low μM concentrations. JAK2 down-regulation by WP1130 was a rapid process which could not inhibited by proteasomal, lysosomal, or other serine/threonine protease inhibitors. Recent results show that WP1130 treatment causes translocation of JAK2 from the soluble cytoplasmic fraction into the detergent insoluble fraction. Altered partitioning of JAK2, not direct kinase inhibition, appears to be responsible for the suppression of downstream signaling. Compartmentalization of JAK2 by WP1130 has been seen in most cell lines examined and is distinct from other commercially available JAK2 inhibitors. In vivo studies also show WP1130 has significant anti-tumor effects as compared to parental AG490 compound. Other kinases such as HER2, Btk, Src etc are not effected by WP1130, demonstrating its target specificity. The unique mechanism of WP1130 may be exploited for therapy in many forms of cancers and malignancies where JAK2 plays pivotal role." @default.
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• W3046261291 date "2007-05-01" @default.
• W3046261291 modified "2023-09-28" @default.
• W3046261291 title "Sub-cellular compartmentalization of Jak2 as a unique mechanism for the inhibition of Jak2-Stat3 signaling" @default.
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