FMS-like tyrosine kinase 3 (FLT3) and Janus kinase 2 (JAK2) are tyrosine kinases that mediate cytokine signaling and are frequently mutated in cancers, particularly acute myeloid leukemia.
CAS：937272-79-2
分子式：C28H32N4O3
分子量：472.6
纯度：98%
存储：Store at -20°C

Background:

Pacritinib is a potent inhibitor of both wild-type JAK2 (IC50=23 nM) and JAK2V617F mutant (IC50=19 nM). Pacritinib also inhibits FLT3 (IC50=22 nM) and its mutant FLT3D835Y (IC50=6 nM).

Relative to JAK2, Pacritinib (SB1518) is two-fold less potent against TYK2 (IC50=50 nM), 23-fold less potent against JAK3 (IC50=520 nM) and 56-fold less potent against JAK1 (IC50=1280 nM). The rest of the evaluated kinases show<30% inhibition when tested against 100 nM Pacritinib at adenosine triphosphate concentrations equivalent to its Michaelis constant (Km). Pacritinib inhibits MV4-11 and MOLM-13 cells (both of which are cell lines derived from human acute myeloid leukemias driven by an FLT3 ITD mutation) with IC50 of 47 and 67 nM, respectively. Pacritinib inhibits Karpas 1106P and Ba/F3-JAK2V617F cells (which are cell lines dependent on JAK2 signaling) with IC50 of 348 and 160 nM, respectively[1]. FLT3-ITD harboring MV4-11 cells are treated for 3 h with different concentrations of Pacritinib (SB1518) and pFLT3, pSTAT5 and pERK1/2 levels are quantified. Pacritinib leads to a dose-dependent decrease of pFLT3, pSTAT5, pERK1/2 and pAkt with IC50 of 80, 40, 33 and 29 nM, respectively. The IC50 on auto-phosphorylation of FLT3-wt in RS4;11 is four-fold higher (IC50=600 nM) compare with FLT3-ITD in MV4-11 and MOLM-13 cells. However, STAT5 inhibition is detected at much lower concentrations of Pacritinib (IC50=8 nM)[2].

For evaluation of efficacy in the Ba/F3-JAK2V617F engraftment model, mice are treated with Pacritinib (SB1518) at doses of 50 or 150 mg/kg p.o. q.d. for 13 days, with drug dosing starting 4 days after cell inoculation. At study termination, the vehicle control mice exhibit splenomegaly and hepatomegaly (