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Ma L, Clayton JR, Walgren RA, et al. Discovery and characterization of LY2784544, a small-molecule tyrosine kinase inhibitor of JAK2V617F. Blood Cancer J. 2013;3:e109doi: 10.1038/bcj.2013.6.
Ma, L., Clayton, J. R., Walgren, R. A., Zhao, B., Evans, R. J., Smith, M. C., Heinz-Taheny, K. M., Kreklau, E. L., Bloem, L., Pitou, C., Shen, W., Strelow, J. M., Halstead, C., Rempala, M. E., Parthasarathy, S., Gillig, J. R., Heinz, L. J., Pei, H., Wang, Y., Stancato, L. F., Dowless, M. S., Iversen, P. W., & Burkholder, T. P. (2013). Discovery and characterization of LY2784544, a small-molecule tyrosine kinase inhibitor of JAK2V617F. Blood cancer journal, 3e109. https://doi.org/10.1038/bcj.2013.6
Ma, L, et al. "Discovery and characterization of LY2784544, a small-molecule tyrosine kinase inhibitor of JAK2V617F." Blood cancer journal vol. 3 (2013): e109. doi: https://doi.org/10.1038/bcj.2013.6
Ma L, Clayton JR, Walgren RA, Zhao B, Evans RJ, Smith MC, Heinz-Taheny KM, Kreklau EL, Bloem L, Pitou C, Shen W, Strelow JM, Halstead C, Rempala ME, Parthasarathy S, Gillig JR, Heinz LJ, Pei H, Wang Y, Stancato LF, Dowless MS, Iversen PW, Burkholder TP. Discovery and characterization of LY2784544, a small-molecule tyrosine kinase inhibitor of JAK2V617F. Blood Cancer J. 2013 Apr 12;3:e109. doi: 10.1038/bcj.2013.6. PMID: 23584399; PMCID: PMC3641321.
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Blood Cancer J. 2013 Apr 12;3:e109. doi: 10.1038/bcj.2013.6.

Discovery and characterization of LY2784544, a small-molecule tyrosine kinase inhibitor of JAK2V617F.

Blood cancer journal

L Ma, J R Clayton, R A Walgren, B Zhao, R J Evans, M C Smith, K M Heinz-Taheny, E L Kreklau, L Bloem, C Pitou, W Shen, J M Strelow, C Halstead, M E Rempala, S Parthasarathy, J R Gillig, L J Heinz, H Pei, Y Wang, L F Stancato, M S Dowless, P W Iversen, T P Burkholder

Affiliations

  1. Eli Lilly and Company, Indianapolis, IN, USA.

PMID: 23584399 PMCID: PMC3641321 DOI: 10.1038/bcj.2013.6

Abstract

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<0.05) Ba/F3-JAK2V617F-GFP tumor burden in the JAK2V617F-induced MPN model (TED50=13.7 mg/kg, twice daily). In contrast, LY2784544 showed no effect on erythroid progenitors, reticulocytes or platelets. These data suggest that LY2784544 has potential for development as a targeted agent against JAK2V617F and may have properties that allow suppression of JAK2V617F-induced MPN pathogenesis while minimizing effects on hematopoietic progenitor cells.

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