Background:

Pacritinib is a small molecule inhibitor of Janus kinase 2/Fms-like tyrosine kinase-3 (JAK2/FLT3) with IC50 values of 23nM, 19nM and 22nM, respectively for JAK2WT, JAK2V617F and FLT3 [1].

Pacritinib inhibits the JAK2-mediated production of p-STAT5 and p-STAT3 in Ba/F3 cells and the production of p-FLT3 and p-STAT5 in MV4-11 cells. It is less active against CYP3A4 and has good selectivity and microsomal stability. Pacritinib is proved to be high permeable in a Caco-2 bidirectional permeability assay. Additionally, pacritinib has a good oral bioavailability. In the Ba/F3-JAK2V617F mouse allograft, 150mg/kg treatment of pacritinib significantly alleviates the disease symptoms. In the MV4-11 xenografts, 50mg/kg and 100 mg/kg pacritinib treatments both show a significantly increased median survival of 55 days [1].

参考文献:
[1] William AD, Lee AC, Blanchard S, Poulsen A, Teo EL, Nagaraj H, Tan E, Chen D, Williams M, Sun ET, Goh KC, Ong WC, Goh SK, Hart S, Jayaraman R, Pasha MK, Ethirajulu K, Wood JM, Dymock BW. Discovery of the macrocycle 11-(2-pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triaza-tetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene (SB1518), a potent Janus kinase 2/fms-like tyrosine kinase-3 (JAK2/FLT3) inhibitor for the treatment of myelofibrosis and lymphoma. J Med Chem. 2011 Jul 14;54(13):4638-58.