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| 5mg |
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| 10mg |
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| Targets |
CDK9 (primarily). Voruciclib potently inhibits CDK9, which is the transcriptional regulator of the anti-apoptotic protein Mcl-1. By inhibiting CDK9, it reduces Mcl-1 expression, sensitizing cancer cells to apoptosis. It also shows activity against CDK4/CDK6, contributing to cell cycle arrest.
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| ln Vitro |
Voruciclib inhibits CDK9 with Ki values ranging from 0.626 nM to 9.1 nM. It also shows activity against CDK6/cyclin D1 (Ki = 2.26 nM) and CDK4/cyclin D1 (Ki = 9.1 nM). The compound effectively blocks the transcriptional regulator activity of CDK9, leading to downregulation of Mcl-1 protein expression in multiple cancer cell lines.
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| ln Vivo |
In AML and DLBCL xenograft models, oral administration of Voruciclib hydrochloride leads to significant tumor growth inhibition. It synergizes with venetoclax (BCL-2 inhibitor) in preclinical models. In vivo, it downregulates Mcl-1 within 6 hours post-dose, with sustained target engagement, and reduces leukemia burden in disseminated models, extending survival.
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| Enzyme Assay |
For CDK9 inhibition assays, recombinant active CDK9/Cyclin T1 or CDK9/Cyclin T2 complexes are incubated with a fluorescent peptide substrate (derived from RNA polymerase II CTD) and varying concentrations of Voruciclib in the presence of ATP. After incubation, the reaction is stopped, and fluorescence polarization is measured to calculate Ki values by fitting to a competitive inhibition model.
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| Cell Assay |
Varies by cancer type, but for hematological studies, cell lines such as MV-4-11 (AML), OCI-LY3 (DLBCL) or A375 (melanoma) are used. Cells are treated with Voruciclib (0.01-10 microM) for 24-72 hours. Apoptosis is assessed by Annexin V/PI staining via flow cytometry. Cell cycle distribution is analyzed by propidium iodide staining. Mcl-1 and BCL-2 protein levels are quantified by Western blot.
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| Animal Protocol |
For DLBCL xenografts, female SCID mice are implanted subcutaneously with OCI-LY3 cells. When tumors reach ~150 mm3, mice receive oral Voruciclib hydrochloride (doses 10-50 mg/kg) daily for 14-28 days. For combination studies, Voruciclib is administered alongside venetoclax. Tumor volume and body weight are monitored. Tumors are excised for Western blot analysis of Mcl-1 and cleaved caspase-3.
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| ADME/Pharmacokinetics |
In preclinical species (rats and dogs), Voruciclib is orally bioavailable. It exhibits moderate plasma clearance and a half-life suitable for once-daily dosing. It penetrates tumor tissues effectively. Metabolic stability assays show it is metabolized primarily by CYP3A4. Plasma protein binding is moderate. Drug-drug interaction potential should be considered when combining with CYP3A4 modulators.
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| Toxicity/Toxicokinetics |
In preclinical safety studies, Voruciclib hydrochloride is generally well-tolerated. Adverse effects associated with CDK9 inhibition (e.g., GI disturbances, fatigue) are expected but manageable. In Phase 1 clinical trials, the most common treatment-emergent adverse events were neutropenia, thrombocytopenia, and fatigue. There were no dose-limiting toxicities. No significant cardiac or hepatotoxicity signals were observed.
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| References |
[1]. Veena Agarwal, et al. A synergistic pharmaceutical combination for the treatment of pancreatic cancer. WO2012123889A1.
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| Additional Infomation |
Voruciclib hydrochloride has successfully completed Phase 1 clinical trials in patients with relapsed/refractory acute myeloid leukemia (AML) and B-cell malignancies. The Phase 1 study demonstrated that voruciclib administered on days 1 to 14 in 28-day cycles was well tolerated with no dose-limiting toxicities. It is currently in clinical development for combination therapies, particularly with venetoclax.
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| Molecular Formula |
C22H20CL2F3NO5
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|---|---|
| Molecular Weight |
506.30
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| Exact Mass |
505.067
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| Related CAS # |
Voruciclib;1000023-04-0;Voruciclib hydrochloride;1000023-05-1;rel-(2S,3R)-Voruciclib;1253731-24-6
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| PubChem CID |
24888039
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| Appearance |
Light yellow to yellow solid powder
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| Hydrogen Bond Donor Count |
4
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
33
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| Complexity |
750
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| Defined Atom Stereocenter Count |
2
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| SMILES |
CN1CC[C@@H]([C@H]1CO)C2=C(C=C(C3=C2OC(=CC3=O)C4=C(C=C(C=C4)C(F)(F)F)Cl)O)O.Cl
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| InChi Key |
QCWRANLELLMJSH-DSHXVJGRSA-N
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| InChi Code |
InChI=1S/C22H19ClF3NO5.ClH/c1-27-5-4-12(14(27)9-28)19-15(29)7-16(30)20-17(31)8-18(32-21(19)20)11-3-2-10(6-13(11)23)22(24,25)26;/h2-3,6-8,12,14,28-30H,4-5,9H2,1H3;1H/t12-,14+;/m0./s1
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| Chemical Name |
2-[2-chloro-4-(trifluoromethyl)phenyl]-5,7-dihydroxy-8-[(2S,3R)-2-(hydroxymethyl)-1-methylpyrrolidin-3-yl]chromen-4-one;hydrochloride
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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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