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Voruciclib (formerly known as P1446A-05) is a potent and orally bioavailable CDK4/cyclin-dependent kinase 4 inhibitor with potential anticancer activity. P1446A-05 has CDK inhibitory values ranging from 0.626 nM to 9.1 nM. It specifically prevents the G1-S phase transition mediated by CDK4, which stops cell cycle and stops the growth of cancer cells. The first kinase to activate in response to mitogenic stimulation is the serine/threonine kinase CDK4, which is found in a complex with D-type G1 cyclins. CDK-cyclin complexes have been demonstrated to phosphorylate the retinoblastoma (Rb) transcription factor in early G1, dislodging histone deacetylase (HDAC), and preventing transcriptional repression.
| Targets |
CDK9/cyc T2 (Ki = 0.626 nM); CDK9/CycT1 (Ki = 1.68 nM); CDK6/cycD1 (Ki = 2.92 nM); CDK4/Cyc D1 (Ki = 3.96 nM); CDK1/cycB (Ki = 5.4 nM); CDK1/cyc A (Ki = 9.1 nM)
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| ln Vitro |
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| ln Vivo |
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| Enzyme Assay |
Reaction Biology IC50 profiling[1]
Rank order of sensitivity of 48 kinases to voruciclib hydrochloride was determined at Reaction Biology Corp. Kinase activity was measured using a filter binding assay with radioactive γ-33P-ATP as phosphate donor. The ATP concentration was near the Km values for the respective kinases. For each kinase, an IC50 value was calculated from a 10-point concentration curve of the test article and converted to Ki values. The 48 kinases studied here had been identified in previous screening experiments as the most promising target candidates. |
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| Cell Assay |
Cell Line: U2932, RIVA, OCI-LY10 cells (ABC subtype), NU-DHL-1, SU-DHL-4, SU-DHL-6 cells (GCB subtype)
Concentration: 0.5 µM, 1 µM, 2 µM, 3 µM, 4 µM, 5 µM Incubation Time: 6 hours Result: Showed targeted downregulation of MCL-1 in both ABC and GCB subtypes. |
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| Animal Protocol |
ABC subtypes (U2932, RIVA, OCI-LY10), GCB subtypes (SU-DHL-4, NU-DHL-1) xenografted in Female NOD.CB17-Prkdcscid/NCrHsd mice
200 mpk Oral gavage; U2932, RIVA, SU-DHL-4 (six days per week for 4 weeks), OCI-LY10 (six days per week for 2 weeks), NU-DHL-1 (five days per week for 3 weeks) For systemic drug efficacy studies, mice were enrolled when tumors reached an average volume of 150–200 mm3. Assignment to treatment groups was carried out via stratified randomization. Tumor dimensions were measured twice a week using digital calipers along with recording of body weight. Tumor volume was calculated using formula V = π/6 (length x width x height) in mm3 . Animals were removed from the study when either any one of the three measured dimensions of the tumor exceeded 2 cm, volume exceeded 2000 mm3, ulceration was observed or if body weight loss greater than 20% was recorded. Drug formulations: voruciclib was formulated in 0.1% methylcellulose and venetoclax in 60% phosal 50, 30% PEG 400, 10% ethanol, both administered orally. Control cohorts were administered vehicles of both drugs, and each single agent cohort was administered the vehicle of the other drug. Depending on the assigned treatment, venetoclax (or its vehicle) was followed by voruciclib (or its vehicle) with 30 mins in between administrations to allow for gastric clearance as per veterinary recommendation. Model specific dosing regimens: U2932: venetoclax at 10 mpk twice a week, voruciclib 200 mpk six days per week for a total duration of 4 weeks; RIVA: venetoclax at 1 mpk twice a week, voruciclib 200 mpk six days per week for a total duration of four weeks; OCI-LY10: venetoclax at 25 mpk twice a week, voruciclib 200 mpk six days per week for a total duration of two weeks; NU-DHL-1: venetoclax at 50 mpk once a week, voruciclib at 200 mpk five days per week for a total duration of three weeks; SU-DHL-4: venetoclax at 25 mpk and voruciclib 200 mpk both six days per week for a total duration of four weeks. The venetoclax + voruciclib combination treatment cohort for each model received both drugs at the same doses and frequencies as the corresponding single agents. |
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| References | ||
| Additional Infomation |
Voruciclib is under investigation in clinical trial NCT03547115 (A Phase 1 Study of Voruciclib in Subjects With B-Cell Malignancies or AML).
Voruciclib is a cyclin-dependent kinase (CDK) inhibitor with potential antineoplastic activity. Upon administration, voruciclib selectively inhibits cyclin-dependent kinase 4 (CDK4) and 6 (CDK6). This inhibits retinoblastoma (Rb) protein phosphorylation early in the G1 phase, which prevents CDK-mediated G1-S phase transition and leads to cell cycle arrest. This suppresses DNA replication and decreases tumor cell proliferation. CDK4 and 6 are serine/threonine kinases that are upregulated in many tumor cell types and play a key role in the regulation of cell cycle progression. |
| Molecular Formula |
C22H19CLF3NO5
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|---|---|
| Molecular Weight |
469.8412
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| Exact Mass |
469.09
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| Elemental Analysis |
C, 56.24; H, 4.08; Cl, 7.55; F, 12.13; N, 2.98; O, 17.03
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| CAS # |
1000023-04-0
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| Related CAS # |
Voruciclib hydrochloride;1000023-05-1;(2S,3R)-Voruciclib hydrochloride;rel-(2S,3R)-Voruciclib;1253731-24-6; 1000023-04-0; 2505206-37-9 (malonate)
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| PubChem CID |
67409219
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| Appearance |
Light yellow to yellow solid powder
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| LogP |
4.261
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
32
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| Complexity |
750
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| Defined Atom Stereocenter Count |
2
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| SMILES |
ClC1C=C(C(F)(F)F)C=CC=1C1=CC(C2=C(C=C(C(=C2O1)[C@@H]1CCN(C)[C@@H]1CO)O)O)=O
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| InChi Key |
MRPGRAKIAJJGMM-OCCSQVGLSA-N
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| InChi Code |
InChI=1S/C22H19ClF3NO5/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/t12-,14+/m1/s1
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| Chemical Name |
2-[2-chloro-4-(trifluoromethyl)phenyl]-5,7-dihydroxy-8-[(2R,3S)-2-(hydroxymethyl)-1-methylpyrrolidin-3-yl]chromen-4-one
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| Synonyms |
Voruciclib; 1000023-04-0; Voruciclib [INN]; P1446A-05; 2-[2-chloro-4-(trifluoromethyl)phenyl]-5,7-dihydroxy-8-[(2R,3S)-2-(hydroxymethyl)-1-methylpyrrolidin-3-yl]chromen-4-one; W66XP666AM; CHEMBL3905910; P-1446;
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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 |
| 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: ~50 mg/mL (~106.4 mM)
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.1284 mL | 10.6419 mL | 21.2838 mL | |
| 5 mM | 0.4257 mL | 2.1284 mL | 4.2568 mL | |
| 10 mM | 0.2128 mL | 1.0642 mL | 2.1284 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 |
| NCT03547115 | Recruiting | Drug: voruciclib monotherapy Drug: voruciclib and venetoclax |
Follicular Lymphoma (FL) Acute Myeloid Leukemia (AML) |
MEI Pharma, Inc. | May 31, 2018 | Phase 1 |
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