Journal of Experimental Pharmacology (Aug 2016)
Comprehensive kinase profile of pacritinib, a nonmyelosuppressive Janus kinase 2 inhibitor
Abstract
Jack W Singer,1 Suliman Al-Fayoumi,1 Haiching Ma,2 Rami S Komrokji,3 Ruben Mesa,4 Srdan Verstovsek5 1Translational Medicine, CTI BioPharma Corp., Seattle, WA, 2Department of Research and Development, Reaction Biology, Malvern, PA, 3Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 4Division of Hematology and Medical Oncology, Mayo Clinic Cancer Center, Scottsdale, AZ, 5Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 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
