Pacritinib's Lack of Myelosuppression May Be Due to Lack of JAK1, IRAK1 Inhibition
Profile of pacritinib suggests potential role in the treatment of AML, MDS, and CMML.
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.
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.