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Description: Ribociclib (formerly also known as LEE011, NVP-LEE011) is a potent, orally bioavailable and highly specific inhibitor of CDK4/6 (cyclin-dependent kinase) with IC50s of 10 nM and 39 nM, respectively. As of March 2017, Ribociclib was approved by FDA to treat postmenopausal women with a type of advanced breast cancer. Ribociclib functions via decreasing in phosphorylated RB and FOXM1. When tested with 17 human neuroblastoma cell lines, 12 of them were sensitive to Ribociclib treatment with mean IC50=306±68 NM. Treatment with Ribociclib could dramatically decrease cell growth via arresting cell cycle G0-G1. In 12 of 17 human neuroblastoma-derived cell lines, treatment with LEE011 could significantly reduce cell proliferation.
References: Clin Cancer Res. 2013 Nov 15;19(22):6173-82.
Related CAS#: 1374639-79-8 (succinate hydrate); 1211443-80-9 (HCl); 1374639-75-4 (succinate); 1211441-98-3 (free base)
Ribociclib; LEE011; LEE-011; LEE 011; trade name: Kisqali
Chemical Name: 7-cyclopentyl-N,N-dimethyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide
Exact Mass: 434.25426
Mass (g) = Concentration (mol/L) × Volume (L) × Molecular Weight (g/mol)
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
This equation is commonly abbreviated as: C1V1 = C2V2
In vitro activity: LEE011, as dual CDK4/CDK6 inhibitor, significantly inhibits the growth of 12 of 17 neuroblastoma cell lines with mean IC50 of 307 nM. The growth inhibition of neuroblastoma cell lines is primarily cytostatic and is mediated by a G1 cell-cycle arrest and cellular senescence.
Kinase Assay: Ribociclib (formerly also known as LEE011, NVP-LEE011; trade name: Kisqali) is a potent, orally available and highly specific inhibitor of CDK4/6 (cyclin-dependent kinase) with IC50s of 10 nM and 39 nM, respectively. As of March 2017, Ribociclib was approved by FDA to treat postmenopausal women with a type of advanced breast cancer. Ribociclib functions via decreasing in phosphorylated RB and FOXM1. When tested with 17 human neuroblastoma cell lines, 12 of them were sensitive to Ribociclibtreatment with mean IC50=306±68 NM. Treatment with Ribociclib could dramatically decrease cell growth via arresting cell cycle G0-G1. In 12 of 17 human neuroblastoma-derived cell lines, treatment with LEE011 could significantly reduce cell proliferation.
Cell Assay: A panel of neuroblastoma cell lines, selected based upon prior demonstration of substrate adherent growth, is plated in triplicate on the Xcelligence Real-Time Cell Electronic Sensing system and treated 24 hours later with a four-log dose range of inhibitor or with a dimethyl sulfoxide (DMSO) control. Cell indexes are monitored continuously for ~100 hours, and IC50 values are determined as follows: growth curves are generated by plotting the cell index as a function of time and are 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 posttreatment is then calculated using a baseline area of 1 (the cell index at the time of treatment). Areas are normalized to the DMSO control, and the resulting data are analyzed using a nonlinear log inhibitor versus normalized response function. All experiments are repeated at least once.
Purity ≥98%
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Pharmacologic inhibition of CDK4/6 suppresses neuroblastoma growth in vitro. (A) The growth of 12 of 17 neuroblastoma cell lines was significantly impaired in response to CDK4/6 inhibition with LEE011 (mean IC50 = 306 ± 68 nM, sensitive lines only). Data are plotted (and tabulated) as the best fit IC50 per log(inhibitor) vs. normalized response analysis (GraphPad); upper and lower bars represent 95 % confidence levels. (B) Dose-dependent decreases in pRBS780 accompany growth suppression in sensitive lines and are indicative of on- target activity. Clin Cancer Res. 2013 Nov 15;19(22):6173-82.
Growth suppression via CDK4/6 inhibition is mediated by cell cycle arrest and senescence. Neuroblastoma cell lines with demonstrated sensitivity or resistance to LEE011 were analyzed for cell cycle arrest and senescence associated β-galactosidase (SA-β-gal) activity. (A) A significant G1arrest accompanied by reductions in the fraction of cells in S phase and G2/M was observed in sensitive lines only. (B) Representative cell cycle histograms of a sensitive and resistant cell line. (C)Down-regulation of FOXM1 mRNA and (D) protein was observed in sensitive lines and was associated with (E) the induction of a senescent phenotype. Clin Cancer Res. 2013 Nov 15;19(22):6173-82.
Inhibition of CDK4/6 suppresses neuroblastoma growth in vivo. (A) Mice with subcutaneously implanted xenografts were treated daily with 200 mg/kg LEE011 or with a vehicle for 21 days. In two of three neuroblastoma xenograft models, treatment with LEE011 significantly reduced tumor burden in comparison to vehicle, as determined by linear mixed effects analysis (BE2C, p<0.0001; 1643, p <0.0001; EBC1 p = 0.51). (B) The reduction in tumor proliferation observed in sensitive lines was confirmed by Ki67 staining of resected xenografts, and inhibition of CDK4/6 activity was confirmed by (C) immunohistochemical staining and western blot for pRBS780. Clin Cancer Res. 2013 Nov 15;19(22):6173-82.