Discovery and characterization of LY2784544, a small-molecule tyrosine kinase inhibitor of JAK2V617F
| Autor: | C Halstead, K M Heinz-Taheny, W Shen, Huaxing Pei, Liandong Ma, Louis Stancato, Celine Pitou, Emiko L. Kreklau, Gillig James Ronald, Baohui Zhao, Burkholder Timothy P, L J Heinz, R J Evans, Yong Wang, John Strelow, Michele Dowless, Michele C. Smith, Saravanan Parthasarathy, Laura J. Bloem, Richard A. Walgren, Mark Edward Rempala, Joshua Ryan Clayton, Phillip W Iversen |
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| Rok vydání: | 2013 |
| Předmět: |
Janus kinase 2
biology medicine.drug_class Cell growth Kinase food and beverages Hematology Molecular biology Tyrosine-kinase inhibitor LY2784544 Oncology In vivo Immunology medicine biology.protein Phosphorylation hematologic malignancy Original Article Tyrosine JAK2 inhibition JAK2V617F Tyrosine kinase |
| Zdroj: | Blood Cancer Journal |
| ISSN: | 2044-5385 |
| Popis: | Owing to the prevalence of the JAK2V617F mutation in myeloproliferative neoplasms (MPNs), its constitutive activity, and ability to recapitulate the MPN phenotype in mouse models, JAK2V617F kinase is an attractive therapeutic target. We report the discovery and initial characterization of the orally bioavailable imidazopyridazine, LY2784544, a potent, selective and ATP-competitive inhibitor of janus kinase 2 (JAK2) tyrosine kinase. LY2784544 was discovered and characterized using a JAK2-inhibition screening assay in tandem with biochemical and cell-based assays. LY2784544 in vitro selectivity for JAK2 was found to be equal or superior to known JAK2 inhibitors. Further studies showed that LY2784544 effectively inhibited JAK2V617F-driven signaling and cell proliferation in Ba/F3 cells (IC50=20 and 55 nM, respectively). In comparison, LY2784544 was much less potent at inhibiting interleukin-3-stimulated wild-type JAK2-mediated signaling and cell proliferation (IC50=1183 and 1309 nM, respectively). In vivo, LY2784544 effectively inhibited STAT5 phosphorylation in Ba/F3-JAK2V617F-GFP (green fluorescent protein) ascitic tumor cells (TED50=12.7 mg/kg) and significantly reduced (P |
| Databáze: | OpenAIRE |
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