SAN FRANCISCO—The kinase inhibition profile of pacritinib suggests the drug’s potential role in the treatment of acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and especially chronic myelomonocytic leukemia (CMML), a study (Abstract 1874) presented at the 56th American Society of Hematology (ASH) Annual Meeting and Exposition has shown.

Pacritinib is a JAK2, JAK2 V617F, and FLT3 kinase inhibitor currently in phase 3 development for the treatment of myelofibrosis. The drug is unique in that it does not cause myelosuppression at doses that inhibited the JAK2/STAT3 signaling pathway and resulted in significant efficacy in both non-Hodgkin lymphoma and myelofibrosis.

To better understand the mechanisms that ultimately cause pacritinib’s lack of myelosuppression, researchers conducted a kinome screening analysis against 429 recombinant kinases at a concentration of 100 nM of pacritinib. The researchers then titrated 1 to 100 nM against those kinases that were at least 50% inhibited at 100 nM.

Results showed that pacritinib did not affect JAK1, but did inhibit JAK2, JAK2 V617F, JAK3, FLT3, FLT3-ITD, FLT3 D835Y, TYK2, IRAK1, HIPK4, FMS, and certain c-KIT mutations. The findings suggest that pacritinib’s lack of myelosuppression may be due to JAK2 inhibition without JAK1 inhibition or inhibition of inflammatory signaling through IRAK1, an interleukin-1 receptor kinase.


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The researchers note that pacritinib may be particularly useful for the treatment of CMML because there is an upregulation of JAK2, c-FMS, and IRAK1 in CMML.

Reference

  1. Singer, Jack, MD, et al. “1874 Comprehensive Kinase Profile of Pacritinib, a Non-Myelosuppressive JAK2 Kinase Inhibitor in Phase 3 Development in Primary and Post ET/PV Myelofibrosis.” ASH 2014. Oral Presentation. December 6, 2014.