[Description]:
CHZ868 is a type II JAK2 inhibitor with an IC50 of 0.17 μM in EPOR JAK2 WT Ba/F3 cell.
[Related Catalog]:
[Target]
[In Vitro]
CHZ868 potently inhibits constitutive JAK2 and STAT5 phosphorylation in JAK2V617F SET2 cells. CHZ868 potently inhibits the proliferation of SET2 cells (GI50=59nM), and has 6-fold less growth inhibitory activity against CMK cells (GI50=378nM)[1]. At 100 nM CHZ868 has activity against 26 kinases, including JAK2 and TYK2. CHZ868 is thought to engage with the hinge region of JAK2 through two H-bonds, formed between the amino-pyridine of CHZ868 and the backbone-NH/CO of L932, while the pyridine is occupying the adenine pocket of the ATP binding site. CHZ868 potently suppresses the growth of CRLF2-rearranged human B-ALL cells, abrogates JAK2 signaling[2].
[In Vivo]
CHZ868 is characterized by high passive permeability, good metabolic stability, and low water solubility, as well as by moderate blood clearance and good oral bioavailability, making it suitable for in vivo use. CHZ868 improves survival in mice with human or murine B-ALL. CHZ868 and dexamethasone synergistically induces apoptosis in JAK2-dependent B-ALLs and further improves survival compared to CHZ868 alone[2].
[Cell Assay]
CHZ868 is dissolved in DMSO to make 10 mM stock solution and diluted in culture media. Cells are treated with CHZ868 (0, 0.05, 0.1, 0.2 μM) or vehicle (DMSO). After 48 hr (Ba/F3 cells) or 72 hr (MHH-CALL4 and PDX cells), CellTiter-Glo Luminescent Cell Viability Assay is added (10 μL undiluted or 25 μL of a 1:2 dilution in each well) and plates are read[2].
[Animal admin]
Mice: CHZ868 is reconstituted in 0.5% methylcellulose / 0.5% Tween-80 and administered at doses of 10 or 30 mg/kg/day by oral gavage. Pharmacokinetic/pharmacodynamic and efficacy studies in the mouse model of rhEpo-induced polycythemia are carried out essentially as reported. Detection of STAT5 phosphorylation in spleen lysates by Meso Scale Discovery is performed[2].
[References]
[Related Small Molecules]