Pacritinib (SB1518) 937272-79-2

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Molecular Weight:

472.58 Pacritinib (SB1518) is a potent and selective inhibitor of Janus Kinase 2 (JAK2) and Fms-Like Tyrosine Kinase-3 (FLT3) with IC50s of 23 and 22 nM, respectively. Phase 3.


Biological Activity


Pacritinib is a Potent Inhibitor of both wild-type JAK2 and JAK2V617F mutant (IC50= 19 nM) that is present in high frequencies among patients
with MPD. Relative to JAK2, Pacritinib 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). Pacritinib effectively
permeates cells to modulate signaling pathways downstream of JAK2,
whether agonist activated or mutationally activated.


Pacritinib induces
Apoptosis, Cell Cycle arrest and antiproliferative effects in JAK2WT- and JAK2V617F-dependent cells. Pacritinib inhibits cell proliferation of Karpas 1106P and Ba/F3-JAK2V617F with IC50 of 348 and 160 nM, respectively. Pacritinib inhibits
endogenous colony growth derived from erythroid and myeloid progenitors
with IC50 of 63 and 53 nM , respectively. SB1518 also
inhibits FLT3 and its mutant FLT3-D835Y(IC50= 6 nM ).


Pacritinib
inhibits FLT3 phosphorylation and downstream STAT, MAPK and PI3K
signaling in FLT3-internal-tandem duplication (ITD), FLT3-wt cells and
primary AML blast cells. Pacritinib treatment leads to a dose-dependent
decrease of pFLT3, pSTAT5, pERK1/2 and pAkt in FLT3-ITD harboring MV4-11
cells with IC50 of 80, 40, 33 and 29 nM , respectively. Treatment of
the primary AML blast cells with Pacritinib for 3 h leads to a
dose-dependent decrease of pFLT3, pSTAT3 and pSTAT5 with an IC50 below
0.5 μM.


Pacritinib induces apoptosis, cell cycle arrest and
anti-proliferative effects in FLT3-mutant and FLT3-wt cells. Pacritinib
inhibits cell proliferation of FLT3-ITD-harboring cells MV4-11 and
primary AML blast cells with IC50s of 47 nM and 0.19-1.3 μM,
respectively.


Pacritinib administrated at 150 mg/kg p.o. q.d. to JAK2V617F-dependent
xenograft model, significantly ameliorates splenomegaly and
hepatomegaly symptoms, with 60% normalization of spleen weight and 92%
normalization of liver weight and is well tolerated without significant
weight loss or any hematological toxicities, including thrombocytopenia
and anemia.


Pacritinib induces dose-dependent inhibition of tumor
growth of JAK2V617F-dependent SET-2 xenograft model (40% for 75 mg/kg and 61% for 150 mg/kg). Pacritinib is efficacious in FLT3-ITD-bearing MV4-11 xenograft models.
Pacritinib treated once daily for 21 consecutive days, induces
dose-dependent inhibition of tumor growth (38% for 25 mg/kg, 92% for 50
mg/kg and 121% for 100 mg/kg). Complete regression is observed in 3/10
and 8/8 mice for the 50 and 100 mg/kg/day groups, respectively.

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Product Categories : Epigenetics > JAK Inhibitor