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Purity: ≥98%
Ribociclib HCl (formerly also known as LEE-011, NVP-LEE011; Kisqali), the hydrochloride salt of Ribociclib, is an orally bioavailable CDK4/6 (cyclin-dependent kinase) inhibitor (IC50s = 10 nM and 39 nM) approved in March 2017 by FDA to treat postmenopausal women with a type of advanced breast cancer. Ribociclib works by reducing FOXM1 and phosphorylated RB.
| Targets |
CDK4 (IC50 = 10 nM); CDK6 (IC50 = 39 nM)
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|---|---|
| ln Vitro |
Treating a panel of 17 neuroblastoma cell lines with Ribociclib (LEE011) across a four-log dose range (10 to 10,000 nM). In 12 of the 17 neuroblastoma cell lines that were studied, treatment with ribociclib dramatically reduces substrate adherent growth in comparison to the control (mean IC50=306±68 nM, taking only sensitive lines into consideration; sensitivity is defined as an IC50 of less than 1 μM). After being treated with ribofloxacilb, two neuroblastoma cell lines (IMR5 and BE2C) that have been shown to be sensitive to CDK4/6 inhibition accumulate cells in the G0/G1 phase of the cell cycle in a dose-dependent manner. At concentrations of 100 nM (p=0.007) and 250 nM (p=0.01), respectively, of Ribociclib, this G0/G1 arrest becomes significant[2].
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| ln Vivo |
Ribociclib (LEE011; 200 mg/kg) or a vehicle control is administered once daily for 21 days to CB17 immunodeficient mice carrying BE2C, NB-1643 (MYCN amplified, sensitive in vitro), or EBC1 (non-amplified, resistant in vitro) xenografts. Since none of the xenograft models exhibit weight loss or other toxicity indicators, this dosage strategy is well tolerated. During the course of the 21-day treatment period, mice carrying either the BE2C or 1643 xenografts (both, p<0.0001) showed a significant delay in tumor growth, which did not resume after treatment[2].
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| Enzyme Assay |
Ribociclib, a powerful, oral, and highly selective inhibitor of CDK4/6 (cyclin-dependent kinase), with IC50s of 10 nM and 39 nM, respectively, was previously known as LEE011, NVP-LEE011; trade name: Kisqali. In March 2017, the FDA approved Ribociclib as a treatment for postmenopausal women who had an advanced form of breast cancer. Ribociclib works by reducing the levels of phosphorylated FOXM1 and RB. Out of 17 human neuroblastoma cell lines tested, 12 showed sensitivity to ribofacilb treatment (mean IC50=306±68 NM). By stopping the G0-G1 cell cycle, ribociclib treatment may significantly reduce the rate of cell proliferation. Treatment with LEE011 could markedly inhibit cell proliferation in 12 out of 17 human neuroblastoma-derived cell lines.
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| Cell Assay |
In 35 mm plates, cells are grown for 24 hours, then treated with 500 nM Ribociclib for 6 days. The cells are then fixed, and overnight staining is done. Then, using an Axio Observer D.1 phase contrast microscope, cells are imaged for SA-β-gal. By counting the number of positive cells in three different microscope frames and normalizing to the control, one can calculate the percentage of SA-β-gal positive cells. In order to evaluate apoptotic activity, cells are treated with Ribociclib, plated in triplicate in 96-well plates, and then 16 hours later, caspase 3/7 activation is measured 16 hours after Caspase-Glo 3/7 treatment. As a positive control, SN-38-treated cells are employed[2].
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| Animal Protocol |
Mice: The xenografts derived from BE2C, NB-1643, or EBC1 cell lines are subcutaneously implanted into the right flank of CB17 SCID-/-mice. Then, for a total of 21 days, animals with engrafted tumors measuring 200–600 mm3 are randomly assigned to receive oral treatment with 200 mg/kg Ribociclib in 0.5% methylcellulose (n = 10) or vehicle (n = 10). Throughout the course of treatment, the tumor burden is calculated on a regular basis using the formula (π/6)×d2, where d is the mean tumor diameter measured with a caliper.
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| References |
| Molecular Formula |
C23H31CLN8O
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|---|---|
| Molecular Weight |
471.01
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| Exact Mass |
470.2309353
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| Elemental Analysis |
C, 58.65; H, 6.63; Cl, 7.53; N, 23.79; O, 3.40
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| CAS # |
1211443-80-9
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| Related CAS # |
Ribociclib;1211441-98-3;Ribociclib-d6 hydrochloride;Ribociclib succinate;1374639-75-4;Ribociclib succinate hydrate;1374639-79-8
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| Appearance |
Yellow solid powder
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| SMILES |
CN(C)C(=O)C1=CC2=CN=C(N=C2N1C3CCCC3)NC4=NC=C(C=C4)N5CCNCC5.Cl
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| InChi Key |
JZRSIQPIKASMEV-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C23H30N8O.ClH/c1-29(2)22(32)19-13-16-14-26-23(28-21(16)31(19)17-5-3-4-6-17)27-20-8-7-18(15-25-20)30-11-9-24-10-12-30;/h7-8,13-15,17,24H,3-6,9-12H2,1-2H3,(H,25,26,27,28);1H
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| Chemical Name |
7-cyclopentyl-N,N-dimethyl-2-[(5-piperazin-1-ylpyridin-2-yl)amino]pyrrolo[2,3-d]pyrimidine-6-carboxamide;hydrochloride
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| Synonyms |
NVP-LEE011; LEE011; LEE-011; LEE011 HCl; LEE-011 HCl; LEE 011 HCl; trade name: Kisqali
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 0.77 mg/mL (1.63 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 7.7 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 0.77 mg/mL (1.63 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 7.7 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: 1 mg/mL (2.12 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication (<60°C). |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.1231 mL | 10.6155 mL | 21.2310 mL | |
| 5 mM | 0.4246 mL | 2.1231 mL | 4.2462 mL | |
| 10 mM | 0.2123 mL | 1.0615 mL | 2.1231 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT03237390 | Completed | Drug: Ribociclib Other: Pharmacological Study |
Advanced Malignant Solid Neoplasm Metastatic Malignant Solid Neoplasm |
Mayo Clinic | January 4, 2018 | Phase 1 |
| NCT03009201 | Completed | Drug: Ribociclib Drug: Doxorubicin Hydrochloride |
Myxofibrosarcoma Unresectable Liposarcoma |
OHSU Knight Cancer Institute | March 10, 2017 | Phase 1 |
| NCT02414724 | Terminated | Drug: Ribociclib Drug: Gemcitabine Hydrochloride |
Lymphoma Solid Neoplasm |
Roswell Park Cancer Institute | May 2015 | Phase 1 |
Pharmacologic inhibition of CDK4/6 suppresses neuroblastoma growthin 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 IC50per log(inhibitor) vs. normalized response analysis (GraphPad); upper and lower bars represent 95 % confidence levels.(B)Dose-dependent decreases in pRBS780accompany growth suppression in sensitive lines and are indicative of on- target activity.Clin Cancer Res.2013 Nov 15;19(22):6173-82. |
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 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 growthin 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. |
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