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J Exp Pharmacol. 2016 Aug 16;8:11-9. doi: 10.2147/JEP.S110702. eCollection 2016.

Comprehensive kinase profile of pacritinib, a nonmyelosuppressive Janus kinase 2 inhibitor.

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Translational Medicine, CTI BioPharma Corp., Seattle, WA.
Department of Research and Development, Reaction Biology, Malvern, PA.
Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.
Division of Hematology and Medical Oncology, Mayo Clinic Cancer Center, Scottsdale, AZ.
Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.


Pacritinib, potent inhibitor of Janus kinase 2 (JAK2), JAK2V617F, and fms-like receptor tyrosine kinase 3, is in Phase III development in myelofibrosis. Among type 1 inhibitors, pacritinib shows a lack of myelosuppression at doses that both inhibit JAK2/signal transducer and activator of transcription 3 pathway and demonstrate clinical efficacy. To elucidate these mechanisms and identify other disease targets, a kinome analysis screened 439 recombinant kinases at 100 nM pacritinib concentration. For kinases with >50% inhibition, pacritinib was titrated from 1 to 100 nM. JAK2, JAK2V617F, FLT3, colony-stimulating factor 1 receptor, and interleukin-1 receptor-associated kinase 1 achieved half-maximal inhibitory concentrations <50 nM. Pacritinib did not inhibit JAK1 (82% control at 100 nM). Lack of myelosuppression may stem from inhibiting JAK2 without affecting JAK1 and reducing hematopoietic inhibitory cytokines by suppressing interleukin-1 receptor-associated kinase 1 or colony-stimulating factor 1 receptor. The pacritinib kinome suggests therapeutic utility in acute myeloid leukemia, myelodysplastic syndrome, chronic myelomonocytic leukemia, solid tumors, and inflammatory conditions.


JAK2V617F; Janus kinase 2; fms-like receptor tyrosine kinase 3; hematologic malignancies; kinase analysis; myelofibrosis

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