Physicochemical Properties
| Molecular Formula | C27H32F2N8O |
| Molecular Weight | 522.592791557312 |
| Exact Mass | 522.27 |
| Elemental Analysis | C, 62.05; H, 6.17; F, 7.27; N, 21.44; O, 3.06 |
| CAS # | 2138499-06-4 |
| Related CAS # | Abemaciclib metabolite M20-d8 |
| PubChem CID | 139600311 |
| Appearance | Light yellow to yellow solid powder |
| LogP | 2.6 |
| Hydrogen Bond Donor Count | 2 |
| Hydrogen Bond Acceptor Count | 10 |
| Rotatable Bond Count | 8 |
| Heavy Atom Count | 38 |
| Complexity | 744 |
| Defined Atom Stereocenter Count | 0 |
| InChi Key | KUJBDJBMXOTNIT-UHFFFAOYSA-N |
| 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) |
| 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 |
| 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 |
| HS Tariff Code | 2934.99.9001 |
| 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) |
Biological Activity
| Targets | CDK4/6; Abemaciclib metabolite |
| 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. |
| ADME/Pharmacokinetics | Pharmacokinetic (PK) evaluations included assessing plasma concentrations of abemaciclib and its metabolites by liquid chromatography–mass spectrometry (LC-MS) method. The median abemaciclib tmax after a single dose was 5.7 hours (range, 3.9-8.0 hours) (Figure 1B). The mean (coefficient of variation) steady-state abemaciclib trough concentration was 364 ng/mL (85%), indicating a high degree of interindividual variability in exposure. After single and multiple doses of abemaciclib, the mean accumulation ratio based on Cmax was 2.14 for abemaciclib and 3.91 to 5.17 for its metabolites, LSN2839567, LSN3106726, and LSN3106729 (Online Supplementary Table S3).[2] |
| References |
[1]. WO2017180389A1. [2]. Haematologica. 2021 Mar 1;106(3):859-862. |
| Additional Infomation |
Mantle cell lymphoma (MCL) accounts for ~6% of all non-Hodgkin lymphomas (NHL) with an aggressive clinical course in patients, especially after early relapse. Lack of cure for relapsed/refractory (R/R) MCL with conventional therapy has resulted in a search for targeted therapies. CDK4 and CDK6 inhibitors have emerged as therapeutic options for R/R MCL because MCL cell lines and patient-derived samples that express high levels of cyclin D1 are highly sensitive to CDK4 and CDK6 inhibitors. Oral abemaciclib is a potent and selective CDK4 and CDK6 inhibitor that reduced tumor growth in human xenograft models with MCL. In a phase I study of patients with MCL, palbociclib, another CDK4 and CDK6 inhibitor, was shown to overcome resistance to ibrutinib, a first-in-class bruton tyrosine kinase (BTK) inhibitor. Here, we evaluated the efficacy, safety, and pharmacokinetic profile of abemaciclib in patients with R/R MCL in a phase II trial.[2]
In conclusion, this study demonstrated that singleagent abemaciclib dosed on a continuous schedule has clinical activity in patients with R/R MCL who received multiple prior systemic therapies. The safety profile of abemaciclib in this patient group is generally consistent with other abemaciclib studies on advanced breast cancer except for higher thrombocytopenia. Additional clinical trials of abemaciclib in combination with current preferred therapies such as a BTK inhibitors are needed to determine the synergistic effects and positioning of CDK4 and CDK6 inhibitors in MCL.[2] |
Solubility Data
| Solubility (In Vitro) | DMSO: ~5 mg/mL (~9.6 mM) |
| 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 (e.g. IP/IV/IM/SC) Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline) *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). 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)] *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. Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline) Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline) Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline) Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil) Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL 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). Oral Formulation 3: Dissolved in PEG400 Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose Oral Formulation 6: Mixing with food powders Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently. (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 |