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

Jack W. Singer, Suliman Al-Fayoumi, Haiching Ma, Rami S. Komrokji, Ruben Mesa, Srdan Verstovsek

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)11-19
Number of pages9
JournalJournal of Experimental Pharmacology
Volume8
DOIs
StatePublished - Aug 16 2016

Keywords

  • FMS-like receptor tyrosine kinase 3
  • Hematologic malignancies
  • JAK2V617F
  • Janus kinase 2
  • Kinase analysis
  • Myelofibrosis

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology
  • Pharmacology (medical)

Fingerprint Dive into the research topics of 'Comprehensive kinase profile of pacritinib, a nonmyelosuppressive janus kinase 2 inhibitor'. Together they form a unique fingerprint.

Cite this