Abstract
We report the characterization of BMS-911543, a potent and selective small-molecule inhibitor of the Janus kinase (JAK) family member, JAK2. Functionally, BMS-911543 displayed potent anti-proliferative and pharmacodynamic (PD) effects in cell lines dependent upon JAK2 signaling, and had little activity in cell types dependent upon other pathways, such as JAK1 and JAK3. BMS-911543 also displayed anti-proliferative responses in colony growth assays using primary progenitor cells isolated from patients with JAK2V617F-positive myeloproliferative neoplasms (MPNs). Similar to these in vitro observations, BMS-911543 was also highly active in in vivo models of JAK2 signaling, with sustained pathway suppression being observed after a single oral dose. At low dose levels active in JAK2-dependent PD models, no effects were observed in an in vivo model of immunosuppression monitoring antigen-induced IgG and IgM production. Expression profiling of JAK2V617F-expressing cells treated with diverse JAK2 inhibitors revealed a shared set of transcriptional changes underlying pharmacological effects of JAK2 inhibition, including many STAT1-regulated genes and STAT1 itself. Collectively, our results highlight BMS-911543 as a functionally selective JAK2 inhibitor and support the therapeutic rationale for its further characterization in patients with MPN or in other disorders characterized by constitutively active JAK2 signaling.
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Acknowledgements
We thank Dr Gary Gilliland for the kind gift of the Ba/F3-engineered cell lines. This work was supported by Bristol-Myers Squibb.
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AVP, TMM, HW, DY, BP, XH, RV, YZ, SUR, GLT, LL, MMG, PRM, HS, JH, SLE, YB, EF, TLT KWM, EM, CM, FYL, AW and MVL are employees of Bristol-Myers Squibb, which generated BMS-911543 for clinical trials. All other authors declare no conflict of interest.
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Purandare, A., McDevitt, T., Wan, H. et al. Characterization of BMS-911543, a functionally selective small-molecule inhibitor of JAK2. Leukemia 26, 280–288 (2012). https://doi.org/10.1038/leu.2011.292
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DOI: https://doi.org/10.1038/leu.2011.292
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