| References: |
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). 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.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. |
