파클리니브

한글명:파클리니브

카스 번호937272-79-2

상품명:PACRITINIB

CBNumberCB82628224

분자식C28H32N4O3

포뮬러 무게472.58

MOL 파일937272-79-2.mol

동의어(한글)

파클리니브

화학적 성질

끓는 점	694.3±65.0 °C(Predicted)
밀도	1.22±0.1 g/cm3(Predicted)
저장 조건	Store at -20°C
용해도	DMSO:5.0(Max Conc. mg/mL);10.6(Max Conc. mM)
물리적 상태	결정성 고체
산도 계수 (pKa)	9.56±0.20(Predicted)

그림문자(GHS)

파클리니브 화학적 특성, 용도, 생산

Characteristics
Class: non-receptor tyrosine kinase (JAK3)
Treatment: myelofibrosis
Elimination half-life = 40 h
Protein binding = 99%
용도
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.
효소 저해제
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.

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