ON123300 is a potent and multi-targeted kinase inhibitor which inhibits CDK4, Ark5, PDGFRβ, FGFR1, RET, and Fyn with IC50 of 3.9 nM, 5 nM, 26 nM, 26 nM, 9.2 nM and 11nM respectively.
The cyclin-dependent kinases (CDKs) have a central role in coordinating the eukaryotic cell division cycle, and also serve to integrate diverse growth-regulatory signals[5]. ON123300 is an effective multi-target kinase inhibitor against CDK4 and ARK5, two kinases intimately associated with growth, survival and metastasis of human tumor cells with IC50s of 3.9 nM, 5 nM, respectively. Z138C cells treated with ON123300 for 24 hours accumulated in the G1 phase at lower concentrations (0.1–1.0 µM), at higher concentrations of this compound, a large proportion of the cells progressed through the S and G2/M phases of the cell cycle and eventually accumulated in the sub-G1 phase, suggesting an induction of apoptosis. Granta 519 and Z138C cells were treated with increasing concentrations of ON123300 for 24 hours. ON123300 repressed the phosphorylation of pRb and p130 in a dose-dependent manner suggesting that ON123300 inactivated the Rb (Retinoblastoma family of proteins) pathway due to the inhibition of CDK4 in the two MCL (mantle cell lymphoma) cell lines. Mice with tumor xenografts were randomly assigned into 2 treatment groups and treated daily with either water (vehicle) or ON123300 (100mg/kg) on a daily basis. Treatment with ON123300 significantly inhibited (p<0.05) tumor growth over a 2-week period, suggesting that this compound is a potent inhibitor of MCL proliferation in vivo[6].
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