LEE011 is an orally available, small-molecule inhibitor of cyclin-dependent kinases (CDK) which targeting cyclin D1/CDK4 and cyclin D3/CDK6 cell cycle pathway, with potential antineoplastic activity. CDK4/6 inhibitor LEE011 specifically inhibits CDK4 and 6, thereby inhibiting retinoblastoma (Rb) protein phosphorylation. LEE011 caused cell-cycle arrest and cellular senescence that was attributed to dose-dependent decreases in phosphorylated RB and FOXM1, respectively. In addition, responsiveness of neuroblastoma xenografts to LEE011 translated to the in vivo setting in that there was a direct correlation of in vitro IC50 values with degree of subcutaneous xenograft growth delay. Treatment with LEE011 significantly reduced proliferation in 12 of 17 human neuroblastoma-derived cell lines by inducing cytostasis at nanomolar concentrations (mean IC50 = 307 ± 68 nmol/L in sensitive lines). LEE011 is currently in Phase I development by Novartis.
|Source||Bio Pharma (2018). Figure 5. LEE011|
|Cell Lines||MDCKII-ABCB1, MDCKII-ABCG2, or MDCKII-parent cells|
|Concentrations||12 and 20 μM|
|Incubation Time||72 h|
|Results||The ABCB1 and ABCG2 expression rate was assessed using the ΔΔCt method, and we observed no significant change in the transporter-encoding gene studied, as demonstrated in Figure 5D.|
|Cell lines||MYCN amplified neuroblastoma cell lines|
|Preparation method||Pharmacologic growth inhibition LEE011 was provided by Novartis pharmaceuticals. A panel of neuroblastoma cell lines, selected based upon prior demonstration of substrate adherent growth, was plated in triplicate on the Xcelligence Real-Time Cell Electronic Sensing system (ACEA Biosciences) and treated 24 hours later with a four-log dose range of inhibitor or with a DMSO control. Cell indexes were monitored continuously for ~100 hours, and IC50 values were determined as follows: Growth curves were generated by plotting the cell index as a function of time and were normalized to the cell index at the time of treatment for a baseline cell index of 1. The area under the normalized growth curve from the time of treatment to 96 hours post-treatment was then calculated using a baseline area of 1 (the cell index at the time of treatment). Areas were normalized to the DMSO control, and the resulting data were analyzed using a non-linear log inhibitor vs. normalized response function (Graphpad). All experiments were repeated at least once.|
|Animal models||BE2C, NB-1643, or EBC1 cell line-derived xenografts of CB17 SCID−/− mice|
|Formulation||0.5 % methylcellulose|
|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.
Dual CDK4/CDK6 inhibition induces cell-cycle arrest and senescence in neuroblastoma.
Rader J, et al. Clin Cancer Res. 2013 Nov 15;19(22):6173-82. PMID: 24045179.
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