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Voruciclib hydrochloride, formerly known as P1446A-05, is a potent and orally bioavailable protein kinase inhibitor specific for the cyclin-dependent kinase 4 (CDK4) with potential antineoplastic activity. CDK4 inhibitor P1446A-05 specifically inhibits CDK4-mediated G1-S phase transition, arresting cell cycling and inhibiting cancer cell growth. The serine/threonine kinase CDK4 is found in a complex with D-type G1 cyclins and is the first kinase to become activated upon mitogenic stimulation, releasing cells from a quiescent stage into the G1/S growth cycling stage; CDK-cyclin complexes have been shown to phosphorylate the retinoblastoma (Rb) transcription factor in early G1, displacing histone deacetylase (HDAC) and blocking transcriptional repression.
| ln Vitro |
Targeted downregulation of MCL-1 in ABC and GCB isoforms is shown with voruciclib hydrochloride (0.5–5 µM; 6 hours) [1]. The Ki values are 0.626 nM, 1.68 nM, 2.92 nM, respectively, for each target (e.g., CDK9/cyc T2, CDK9/cyc T1, CDK6/cyc D1, CDK4/cyc D1, CDK1/cyc B, and CDK1/cyc A for Voruciclib hydrochloride)[1].
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| ln Vivo |
Voruciclib hydrochloride (200 mpk; oral gavage) combined with venetoclax (10 mpk, 1 mpk, 50 mpk, 25 mpk in U2932, RIVA, SU-DHL-4, and NU-DHL-1, respectively) enhances tumor growth inhibition In the U2932, RIVA, SU-DHL-4 (6 days per week for 4 weeks) and NU-DHL-1 (5 days per week for 3 weeks) DLBCL models, compared with either drug alone [ 1].
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| Cell Assay |
Western Blot Analysis[1]
Cell Types: U2932, RIVA, OCI-LY10 cells (ABC subtype), NU-DHL-1, SU-DHL-4, SU-DHL-6 cells (GCB subtype) Tested Concentrations: 0.5 µM , 1 µM, 2 µM, 3 µM, 4 µM, 5 µM Incubation Duration: 6 hrs (hours) Experimental Results: Targeted downregulation of MCL-1 was shown in both ABC and GCB subtypes. |
| Animal Protocol |
Animal/Disease Models: ABC isoforms (U2932, RIVA, OCI-LY10), GCB isoforms (SU-DHL-4, NU-DHL-1) xenografted into female NOD.CB17-Prkdcscid/NCrHsd mice [1]
Doses: 200 mpk Doses: po (oral gavage); U2932, RIVA, SU-DHL-4 (6 days per week for 4 weeks), OCI-LY10 (6 days per week for 2 weeks), NU-DHL-1 ( 5 days per week for 3 weeks) Experimental Results: Tumor enhanced growth inhibition in U2932, RIVA, SU-DHL-4 and NU-DHL-1 models in addition to OCI-LY10 model. |
| References |
[1]. Dey J, et al. Voruciclib, a clinical stage oral CDK9 inhibitor, represses MCL-1 and sensitizes high-risk Diffuse Large B-cell Lymphoma to BCL2 inhibition. Sci Rep. 2017 Dec 21;7(1):18007.
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| Molecular Formula |
C₂₂H₂₀CL₂F₃NO₅
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|---|---|
| Molecular Weight |
506.30
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| CAS # |
1000023-05-1
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| Related CAS # |
Voruciclib;1000023-04-0;(2S,3R)-Voruciclib hydrochloride;rel-(2S,3R)-Voruciclib;1253731-24-6
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| Appearance |
Typically exists as solids (or liquids in special cases) at room temperature
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| SMILES |
Cl[H].O=C1C=C(C2=CC=C(C(F)(F)F)C=C2Cl)OC3=C([]4[](CO)N(C)CC4)C(O)=CC(O)=C13
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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) |
DMSO : ≥ 250 mg/mL (~493.78 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.11 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 20.8 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: ≥ 2.08 mg/mL (4.11 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 20.8 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: ≥ 2.08 mg/mL (4.11 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.9751 mL | 9.8756 mL | 19.7511 mL | |
| 5 mM | 0.3950 mL | 1.9751 mL | 3.9502 mL | |
| 10 mM | 0.1975 mL | 0.9876 mL | 1.9751 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.
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