937272-79-2 Usage
Uses
Pacritinib is a JAK2/FLT3 inhibitor used in the treatment of acute myeloid leukemia showing significant tumor growth inhibition and lung metastasis.
Mechanism of action
Pacritinib competes ?with JAK2 for ATP binding, which may result in inhibition of JAK2 ?activation, inhibition of the JAK-STAT signaling pathway, and so ?caspase-dependent apoptosis.
Enzyme inhibitor
This pyrimidine-based macrocycle and potent protein kinase inhibitor (FW = 472.59 g/mol; CAS 937272-79-2; Solubility: 11 mg/mL DMSO), also known as SB1518, selectively targets Janus Kinase 2 (or JAK2; IC50 = 23 nM) and Fms-Like Tyrosine Kinase-3 (or FLT3; IC50 = 22 nM), with values of 1280 and 522 nM for JAK1 and JAK3. FLT3 is genetically altered in up to 35% of acute myeloblastic leukemias, making it an attractive target for AML patients. Pacritinib has potent anti-proliferative effects on myeloid and lymphoid cell lines driven by mutant or wild-type JAK2 or FLT3, resulting from cell cycle arrest and induction of apoptosis. SB1518 has favorable pharmacokinetic properties after oral dosing in mice, is well tolerated and significantly reduces splenomegaly and hepatomegaly in a JAK2(Val-617-Phe)-driven disease model. Primary Mode of Inhibitory Action: Upregulation of JAK2 in FLT3-TKI-resistant AML cells was identified as a potential mechanism of resistance to selective FLT3 inhibition. This resistance could be overcome by pacritinib’s combined inhibition of FLT3 and JAK2 in this cellular model. Pacritinib potently inhibits FLT3 auto-phosphorylation and downstream STAT5, MAPK and PI3K signaling pathways in AML cell lines with highest potency against cells harboring FLT3-ITD mutations. Blockade of FLT3 signaling was also demonstrated in primary AML blasts treated ex vivo with pacritinib. In both cell lines and primary blasts, pacritinib treatment led to the induction of G1 arrest, inhibition of cell proliferation, as well as caspase-dependent apoptosis. The anti-proliferative effects of pacritinib on the FLT3-ITD harboring cell lines MV4-11 (IC50 = 47 nM) and MOLM-13 (IC50 = 67 nM), which have been reported previously,16 are in the same range as the inhibition of intracellular FLT3 signalling.
Check Digit Verification of cas no
The CAS Registry Mumber 937272-79-2 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 9,3,7,2,7 and 2 respectively; the second part has 2 digits, 7 and 9 respectively.
Calculate Digit Verification of CAS Registry Number 937272-79:
(8*9)+(7*3)+(6*7)+(5*2)+(4*7)+(3*2)+(2*7)+(1*9)=202
202 % 10 = 2
So 937272-79-2 is a valid CAS Registry Number.
