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

2016; Dove Medical Press; Volume: Volume 8; Linguagem: Inglês

10.2147/jep.s110702

1179-1454

Jack W. Singer, Suliman Al‐Fayoumi, Haiching Ma, Rami S. Komrokji, Ruben A. Mesa, Srđan Verstovšek,

Kruppel-like factors research

Abstract: 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. Keywords: kinase analysis, myelofibrosis, hematologic malignancies, Janus kinase 2, JAK2V617F, fms-like receptor tyrosine kinase 3