In vitro: ON123300 is a novel kinase inhibitor, inhibits CDK4/6 and PI3K-δ and exhibits potent activity against mantle cell lymphomas (MCLs). ON123300 is a low molecular weight multi-kinase inhibitor identified through a series of screens that supported further analyses for brain tumor chemotherapy. Biochemical assays indicated ON123300 was a strong inhibitor of Ark5 and CDK4 as well as growth factor receptor tyrosine kinases such as Beta-type platelet-derived growth factor receptor [PDGFRβ]. ON123300 inhibited U87 glioma cell proliferation with an IC50 = 3.4 ± 0.1 μM and reduced phosphorylation of Akt, yet it also unexpectedly induced Erk activation; both in a dose- and time-dependent manner that subsequently was attributed to relieving Akt-mediated C-Raf S259 inactivation and activating a p70S6K initiated PI3K negative feedback loop.
|Cell lines||MM1.S and NCI-H929 cells|
|Preparation method||MM1.S and NCI-H929 cells were treated with ON123300/PD-0332991 for 24 hours. Approximately 106 cells of each cell line were harvested (along with untreated controls) after 24 hours of treatment in 12-well plates. Cells were washed with PBS and resuspended in appropriate volume of Annexin binding buffer and then stained with Annexin V Pacific Blue/PI.|
|Incubation time||24 h|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||10 mM in DMSO|
Dual Targeting of CDK4 and ARK5 Using a Novel Kinase Inhibitor ON123300 Exerts Potent Anticancer Activity against Multiple Myeloma.
Perumal D, et al. Cancer Res. 2016 Mar 1;76(5):1225-36. PMID: 26873845.
Dual inhibition of CDK4/Rb and PI3K/AKT/mTOR pathways by ON123300 induces synthetic lethality in mantle cell lymphomas.
Divakar SK, et al. Leukemia. 2016 Jan;30(1):86-93. PMID: 26174628.
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