CHR-6494

Description

CHR-6494 is a haspin protein kinase inhibitor (IC₅₀ = 2 nM) selective over 27 other protein kinases, including Aurora B kinase (IC₅₀ > 1 μM). Haspin is a kinase necessary for mitosis that selectively phosphorylates histone 3 at the threonine 3 residue (H3T3ph). CHR-6494 decreases phosphorylation of H3T3 and arrests the cell cycle in the G₂/M phase, which leads to apoptosis. It showed promising results in a xenograft tumor model.

Uses

CHR6494 is a small-molecule inhibitor of histone kinase haspin, with a wide spectrum of anticancer effects.

General Description

A cell-permeable indazolylimidazopyridazinamine compound that acts as a potent and reversible inhibitor of histone kinase haspin activity (IC₅₀ = 2 nM) with moderate selectivity over TrkA, GSK-3β, PIM1, Cdk1/B and Cdk2/A (% inhibition at 100 nM = 58, 48, 36, 34 and 33, respectively) among a panel of 27-kinases. Shown to block pH3-Thr³, with no effect on pH3-Ser¹⁰ and pH3-Ser²⁸, cause mitotic catastrophe, upregulate BUB1 and cyclin B1 levels, and potently induce apoptosis (IC₅₀ = 473, 500 and 752 nM in HeLa, HCT-116 and MDA-MB-231 cells, respectively). Further, efficiently blocks bFGF-induced sprouting vessel by 70% at 1 μM (chicken embryo aortic arch ring assay) and suppresses tumor growth in HCT-116 xenografted mouse model (50 mg/kg, i.p.).