CHZ868 Chemical Properties

Density 

1.37±0.1 g/cm3(Predicted)

storage temp. 

Store at -20°C

solubility 

DMSO:100.0(Max Conc. mg/mL);236.17(Max Conc. mM)

form 

Solid

pka

13.27±0.70(Predicted)

color 

White to gray

Safety Information

WGK Germany 

WGK 3

Storage Class

11 - Combustible Solids

CHZ868 Usage And Synthesis

Uses

CHZ868 is a type II JAK2 inhibitor with an IC50 of 0.17 μM in EPOR JAK2 WT Ba/F3 cell.

Definition

ChEBI: CHZ868 is a memger of the class of benzimidazoles that is benzimidazole that is substituted by methyl groups at positions 1 and 4, by a 2,4-difluoroanilino group at position 2, and by a (2-acetamidopyridin-4-yl)oxy group at position 5. It is a type II JAK2 inhibitor with antineoplastic activity. It has a role as an EC 2.7.10.2 (non-specific protein-tyrosine kinase) inhibitor and an antineoplastic agent. It is a member of benzimidazoles, a member of acetamides, a member of pyridines, a difluorobenzene, an aromatic ether, a secondary amino compound and an aromatic amine.

Biological Activity

Orally active, type II tyrosine kinase I inhibitor against VEGFR1/2 (FLT1/KDR), PDGFR1/2, KIT, and ROS1 oncogenic fusions/mutations-drivent growth.

CHZ868 is a type II tyrosine kinase inhibitor th at exhibits potent antiproliferation activity against VEGFR1/2 (FLT1/KDR), PDGFR1/2, KIT, and ROS1 TEL fusions-, as well as JAK2 V617F, but not RAF V600E, mutation-driven oncogenic growth (IC50 = 2/11, 4/23, 16, 40, 51 against respective BaF3 transformants) via stablizing target kinases in the inactive “DFG-out” conformation. CHZ868 overcomes Type I JAK inhibitor resistance of JAK2/MPN mutant MPN and JAK2 I682F/CRLF2-rearranged B-ALL cells both in cultures and in mice in vivo (30-40 mg/kg/day p.o.). Comparing to BBT594, CHZ868 is ineffective against BCR-ABL, TEL-FLT3, TEL-RET.

in vivo

IC 50

JAK2: 110 nM (IC₅₀)

References

[1] Meyer SC, et al. CHZ868, a Type II JAK2 Inhibitor, Reverses Type I JAK Inhibitor Persistence and Demonstrates Efficacy in Myeloproliferative Neoplasms. Cancer Cell. 2015 Jul 13;28(1):15-28. DOI:10.1016/j.ccell.2015.06.006
[2] Wu SC, et al. Activity of the Type II JAK2 Inhibitor CHZ868 in B Cell Acute Lymphoblastic Leukemia. Cancer Cell. 2015 Jul 13;28(1):29-41. DOI:10.1016/j.ccell.2015.06.005