PACRITINIB |CAS 937272-79-2 Chemical Properties

Boiling point:

694.3±65.0 °C(Predicted)

Density 

1.22±0.1 g/cm3(Predicted)

storage temp. 

Store at -20°C

solubility 

DMSO:5.0(Max Conc. mg/mL);10.6(Max Conc. mM)

form 

A crystalline solid

pka

9.56±0.20(Predicted)

color 

Light yellow to yellow

InChIKey

HWXVIOGONBBTBY-ONEGZZNKSA-N

SMILES

C12=CC(=CC=C1)COCC=CCOCC1=CC(=CC=C1OCCN1CCCC1)NC1=NC2=CC=N1 |t:10|

PACRITINIB |CAS 937272-79-2 Usage And Synthesis

Description

Pacritinib received accelerated approval in 2022 for the treatment of adults with intermediate or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis with a platelet count below 50 × 109 /L, which affects 26% of all myelofibrosis patients (~20,000 in the United States). Unlike several other JAK2 inhibitors, pacritinib exhibits good selectivity (~60-fold) for JAK2 over JAK1 while also inhibiting JAK3 with about 25-fold lower potency than JAK2. Pacritinib exhibits equipotent activity against FLT3 (IC50 = 22 nM) and mutant FLT3-D835Y (IC50 = 6?nM) at the same potency range as JAK2 (JAK2 IC50 = 23 nM).

Characteristics

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

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.

Mechanism of action

Pacritinib is unique in that it simultaneously inhibits multiple members of the JAK and FLT signaling pathways and is effective against both wild-type and mutant JAK2 and FLT3 cell lines. Unlike other options for treating MF, Pacritinib does not cause myelosuppression, and the most common side effect is manageable gastrointestinal disease.

Synthesis

First, nitrophenol 33.5 was alkylated with 1,2-bromochloroethane to afford 33.6, and the aryl aldehyde was reduced using sodium borohydride to afford benzyl alcohol 33.7. The alcohol was then alkylated using allyl bromide to afford 33.8 with another terminal olefin for a ring-closing aromatization reaction. The alkyl chloride 33.8 was reacted with pyrrolidine to form the tertiary amine 33.9. Next, the nitro group was reduced using tin chloride to afford aniline 33.10. The final step was to construct the macrocycle via a SNAr reaction between aniline 33.10 and chloropyridine 33.4 and a subsequent ring-closing aromatization reaction using a Grignard second-generation catalyst and complete the synthesis of Pacritinib.

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.

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