| Size | Price | Stock | Qty |
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| 5mg |
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| 10mg |
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| 25mg |
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| 50mg |
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| 100mg |
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| Other Sizes |
| Targets |
CDK4/6; Abemaciclib metabolite
CDK4/6-IN-4 targets cyclin-dependent kinases 4 and 6 (CDK4/6), which are key regulators of the cell cycle. CDK4/6 form complexes with cyclin D1 and phosphorylate the retinoblastoma protein (Rb), leading to progression from G1 to S phase. By inhibiting CDK4/6, CDK4/6-IN-4 prevents Rb phosphorylation and induces G1 cell cycle arrest. Similar to Abemaciclib, its major metabolites inhibit CDK4 and CDK6 with similar potencies in biochemical and cell-based assays. |
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| ln Vitro |
Similar to abemaciclib, its major metabolites, LSN2839567 and LSN3106726, also inhibit CDK4 and CDK6 with similar potencies in in vitro biochemical and cell-based assays and the metabolite exposure achieved in patients with MCL at a dosage of 200 mg twice daily exceeds the 50% inhibition concentration (IC50) for CDK4/cyclin D1 and CDK6/cyclin D1. Thus, the exposure of abemaciclib and its active metabolites is consistent with what is expected to yield biological activity. However, the optimal abemaciclib dose in MCL based on the relationship between exposure, efficacy, and safety requires further elucidation.
In vitro, CDK4/6-IN-4 inhibits CDK4 and CDK6 with similar potencies to Abemaciclib in biochemical and cell-based assays. The metabolite exposure achieved in patients at a dosage of 200 mg twice daily exceeds the IC50 for CDK4/cyclin D1 and CDK6/cyclin D1, indicating that the active metabolites contribute to therapeutic efficacy. The compound is used in cancer research to study CDK4/6 inhibition and cell cycle regulation. |
| ln Vivo |
In vivo, CDK4/6-IN-4 is the major active metabolite of Abemaciclib and contributes to the drug's overall therapeutic effect. The metabolite exposure in patients with mantle cell lymphoma exceeds the IC50 for CDK4/cyclin D1 and CDK6/cyclin D1, consistent with expected biological activity. The compound has been studied in the context of Abemaciclib's clinical activity in various cancers. Comprehensive in vivo data for the metabolite alone are available from the clinical development of Abemaciclib.
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| Enzyme Assay |
For in vitro kinase assays, recombinant CDK4/cyclin D1 and CDK6/cyclin D1 complexes are incubated with a peptide substrate (such as Rb-derived peptide) and ATP in kinase assay buffer. The test compound is added at various concentrations (0.1-1000 nM). Kinase activity is measured using radioactive ATP incorporation or luminescent ADP detection assays. IC50 values are calculated by fitting dose-response curves.
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| Cell Assay |
For cell proliferation assays, cancer cell lines sensitive to CDK4/6 inhibition (such as MCF-7 breast cancer cells or mantle cell lymphoma cell lines) are seeded in 96-well plates and treated with CDK4/6-IN-4 at concentrations ranging from 0.01-10 µM for 72-96 hours. Cell viability is assessed using CellTiter-Glo or MTT assays. IC50 values are calculated from dose-response curves. Rb phosphorylation can be assessed by Western blotting to confirm CDK4/6 inhibition.
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| Animal Protocol |
For in vivo studies, pharmacokinetic assessments include determining plasma concentrations of Abemaciclib and its metabolites using liquid chromatography-mass spectrometry (LC-MS). The median time to peak concentration of Abemaciclib after a single dose is 5.7 hours. The steady-state trough concentration is 364 ng/mL (85% CV). The cumulative ratios of metabolites LSN2839567, LSN3106726, and LSN3106729 range from 3.91 to 5.17.
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| ADME/Pharmacokinetics |
Pharmacokinetic (PK) assessments included determining plasma concentrations of abexicillin and its metabolites using liquid chromatography-mass spectrometry (LC-MS). The median time to peak concentration (tmax) of abexicillin after a single dose was 5.7 hours (range: 3.9–8.0 hours) (Figure 1B). The mean (coefficient of variation) of the steady-state trough concentration of abexicillin was 364 ng/mL (85%), indicating significant inter-individual variability in exposure. Based on the mean cumulative ratio of Cmax after single and multiple doses, the mean cumulative ratio of abexicillin was 2.14, and the mean cumulative ratios of its metabolites LSN2839567, LSN3106726, and LSN3106729 were 3.91 to 5.17 (Online Supplementary Table S3). [2]
CDK4/6-IN-4 is the bioactive metabolite of Abemaciclib and contributes to its pharmacokinetic and pharmacodynamic profile. The compound is soluble in DMSO. Storage is recommended at -20°C for long-term stability. As the active metabolite of an FDA-approved drug, comprehensive PK data are available from the clinical development program of Abemaciclib. |
| Toxicity/Toxicokinetics |
Toxicological data for CDK4/6-IN-4 are available from the clinical development of Abemaciclib, as it is the major active metabolite. The safety profile of the metabolite is encompassed by the overall safety profile of Abemaciclib. Common adverse effects associated with CDK4/6 inhibition include myelosuppression, gastrointestinal disturbances, and fatigue. As a research compound, standard safety precautions should be followed.
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| References | |
| Additional Infomation |
Mantle cell lymphoma (MCL) accounts for approximately 6% of all non-Hodgkin lymphomas (NHL), and its clinical course is rapidly progressive, especially after early relapse. Because conventional therapies are ineffective in treating relapsed/refractory (R/R) MCL, targeted therapies have been sought. CDK4 and CDK6 inhibitors have emerged as a treatment option for R/R MCL because MCL cell lines and patient-derived samples expressing high levels of cyclin D1 are highly sensitive to CDK4 and CDK6 inhibitors. Oral abexicillin is a potent and selective CDK4 and CDK6 inhibitor that has inhibited tumor growth in a human MCL xenograft model. In a phase I study of MCL patients, another CDK4 and CDK6 inhibitor, palbociclib, was shown to overcome resistance to ibrutinib, a first-in-class Bruton's tyrosine kinase (BTK) inhibitor. This study evaluated the efficacy, safety, and pharmacokinetic characteristics of abexicillin in patients with relapsed/refractory mantle cell lymphoma (R/R MCL) in a phase II clinical trial. [2] In summary, this study demonstrated that continuous abexicillin monotherapy is clinically active in R/R MCL patients who have previously received multiple systemic therapies. Except for a higher incidence of thrombocytopenia, the safety profile of abexicillin in this patient population was generally consistent with other studies of abexicillin in advanced breast cancer. More clinical trials of abexicillin in combination with current first-line therapies (such as BTK inhibitors) are needed to determine their synergistic effects and the role of CDK4 and CDK6 inhibitors in MCL. [2]
CDK4/6-IN-4 (Abemaciclib metabolite M20, LSN3106726) is the bioactive metabolite of Abemaciclib and a selective CDK4/6 inhibitor. It inhibits CDK4/6 with similar potency to Abemaciclib and contributes to therapeutic efficacy in cancer treatment. Metabolite exposure in patients at clinical doses exceeds the IC50 for CDK4/cyclin D1 and CDK6/cyclin D1. CDK4/6-IN-4 is a research compound and a known active pharmaceutical metabolite of an approved drug. |
| Molecular Formula |
C27H32F2N8O
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|---|---|
| Molecular Weight |
522.592791557312
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| Exact Mass |
522.27
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| Elemental Analysis |
C, 62.05; H, 6.17; F, 7.27; N, 21.44; O, 3.06
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| CAS # |
2138499-06-4
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| Related CAS # |
Abemaciclib metabolite M20-d8
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| PubChem CID |
139600311
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| Appearance |
Light yellow to yellow solid powder
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| LogP |
2.6
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
10
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| Rotatable Bond Count |
8
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| Heavy Atom Count |
38
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| Complexity |
744
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| Defined Atom Stereocenter Count |
0
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| SMILES |
CCN1CCN(CC1)CC2=CN=C(C=C2)NC3=NC=C(C(=N3)C4=CC5=C(C(=C4)F)N=C(N5C(C)C)CO)F
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| InChi Key |
KUJBDJBMXOTNIT-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C27H32F2N8O/c1-4-35-7-9-36(10-8-35)15-18-5-6-23(30-13-18)32-27-31-14-21(29)25(34-27)19-11-20(28)26-22(12-19)37(17(2)3)24(16-38)33-26/h5-6,11-14,17,38H,4,7-10,15-16H2,1-3H3,(H,30,31,32,34)
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| Chemical Name |
[6-[2-[[5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-yl]amino]-5-fluoropyrimidin-4-yl]-4-fluoro-1-propan-2-ylbenzimidazol-2-yl]methanol
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| Synonyms |
CDK4/6 IN 4; CDK4/6-IN-4; CDK4/6-IN 4; Abemaciclib metabolite M20; 2138499-06-4; CDK4/6-IN-4; LSN3106726; [6-[2-[[5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-yl]amino]-5-fluoropyrimidin-4-yl]-4-fluoro-1-propan-2-ylbenzimidazol-2-yl]methanol; SCHEMBL23387651; CDK4/6 IN-4
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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: ~5 mg/mL (~9.6 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 | 1.9135 mL | 9.5677 mL | 19.1355 mL | |
| 5 mM | 0.3827 mL | 1.9135 mL | 3.8271 mL | |
| 10 mM | 0.1914 mL | 0.9568 mL | 1.9135 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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