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Purity: ≥98%
Ebvaciclib (PF-06873600; PF06873600) is a novel, potent, selective and orally bioavailable pan-inhibitor of cyclin-dependent kinase (CDK) with potential antitumor activity. With Ki values of 0.09 nM, 0.13 nM, and 0.16 nM, respectively, it inhibits CDK2, CDK4, and CDK6. PF-06873600 binds to CDKs specifically and inhibits their activity, exhibiting antineoplastic activity. Tumor cell proliferation is inhibited, apoptosis is induced, and cell cycle arrest results from inhibition of these kinases. Tumor cells often overexpress CDKs, ATP-dependent serine/threonine kinases that are key regulators of cell cycle progression and cellular proliferation.
| Targets |
CDK2 (Ki = 0.1 nM); CDK6 (Ki = 0.1 nM); CDK4 (Ki = 1.2 nM)
CDK2 (Ki = 0.13 nM), CDK4 (Ki = 1.25 nM), CDK6 (Ki = 0.11 nM). CDK1 (Ki = 4.5 nM, resulting in ~35-fold selectivity vs. CDK2). CDK9 (Ki = 19.6 nM, resulting in high selectivity). Also shows activity against CDK2/cyclinE1, CDK4/cyclinD1, and CDK6/cyclinD1 complexes. [1] |
|---|---|
| ln Vitro |
PF-06873600 is an cyclin-dependent kinase 2 (CDK2), CDK4, and CDK6 inhibitor with Ki values of 0.1, 1.2, and 0.1 nM, respectively.
PF-06873600 inhibited phosphorylation of RB1 (at Ser807/811) in OVCAR3 ovarian cancer cells with an EC50 of 19 nM. It inhibited proliferation of OVCAR3 cells with an EC50 of 45 nM. In cellular target engagement assays using triple-negative breast cancer HCC1806 cells, PF-06873600 displaced a covalent probe (XO44) from CDK2 with an OC50 of 9 nM and from CDK1 with an OC50 of 597 nM, demonstrating approximately 60-fold cellular selectivity for CDK2 over CDK1. It induced G1 cell cycle arrest in OVCAR3 cells at concentrations up to ~100 nM, and at higher concentrations caused a mixed G1 and G2 arrest. Notably, CDK4/6 inhibitors like palbociclib showed no activity in these CDK2-driven cell lines. [1] |
| ln Vivo |
In mice bearing OVCAR3 tumors, orally administered PF-06873600 inhibited phosphorylation of RB1 in tumor cells with an EC50 of 40 nM.
Tumor growth inhibition studies showed 90% growth inhibition as a single agent at 50 mg/kg BID oral dosing in the OVCAR3 model. In FBXW7-mutated patient-derived xenograft (PDX) models of non-small cell lung cancer (NSCLC), PF-06873600 (30 mg/kg BID, orally) demonstrated 93% growth inhibition in the CTG-0464 model and 103% growth inhibition in the CTG-0192 model. [1] |
| Enzyme Assay |
Biochemical potency (Ki) for CDK/cyclin kinase complexes was determined using a mobility shift assay (MSA). The assay monitors the phosphorylation of a fluorescently-labeled peptide substrate by the kinase. Reactions were performed in a microfluidic environment and detected using capillary electrophoresis. For CDK6/cyclinD1, reactions contained 3 μM fluorescein-labeled peptide substrate ("Dyrktide") and were initiated with 2 mM ATP after a pre-incubation period. Inhibition constants (Ki) were derived by fitting data to the Morrison equation. Similar MSA formats were used for CDK1, CDK2, CDK4, and CDK9 complexes. For GSK3β, reactions monitored phosphorylation of a different fluorescein-labeled peptide and were initiated with 40 μM ATP. [1]
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| Cell Assay |
Phospho-RB1 ELISA: OVCAR3 cells were seeded and synchronized in G1/S phase by overnight treatment with hydroxyurea. Cells were then treated with the test compound for 1 hour. Cells were lysed and lysates were transferred to ELISA plates pre-coated with an anti-phospho-Ser807/811 RB1 antibody for overnight incubation. After washing, total RB1 was detected using a corresponding antibody, followed by an HRP-tagged secondary antibody and a chemiluminescent substrate. Luminescence was measured, and IC50/EC50 values were calculated. [1]
Anti-proliferation Assay (CyQUANT): OVCAR3 cells were seeded in 96-well plates and treated with test compounds for 6 days. Relative viable cell numbers were determined using a fluorescent nucleic acid stain. Fluorescence was measured, and IC50 values were calculated using non-linear regression curve fitting. [1] Cellular Target Engagement: Kuramochi or HCC1806 cells were pre-incubated with compound, then treated with the broad-spectrum covalent kinase probe XO44. Cells were lysed, and a copper-catalyzed azide-alkyne cycloaddition reaction was performed with a biotin-linked azide. After enrichment with streptavidin beads, elution, and SDS-PAGE, Western blotting was used to quantitate the occupancy of the compound on different CDK isoforms, allowing calculation of OC50 values. [1] |
| Animal Protocol |
Mice-bearing OVCAR3 tumors
50 mg/kg p.o. Single-Dose PK in Mice: PF-06873600 was formulated in 10% N-methyl-2-pyrrolidone (NMP)/40% polyethylene glycol 300 (PEG 300)/50% 10 mM citrate buffer. Mice (n=3) received a single intravenous dose (3 mg/kg) via tail vein or a single oral dose (10 mg/kg) via gavage. Blood samples were collected at specified time points. Plasma concentrations were determined by LC-MS/MS. [1] Single-Dose PK in Dogs: PF-06873600 was formulated for IV administration in 10% NMP/40% PEG 300/50% 10 mM citrate buffer (0.5 mg/mL) and for oral administration in 0.5% methylcellulose with 0.1% surfactant (0.5 mg/mL). Dogs (n=2) received a single IV dose (0.25 mg/kg) via the cephalic vein or a single oral dose (0.5 mg/kg) via gavage. Blood samples were collected serially, and plasma concentrations were determined by LC-MS/MS. [1] Tumor Growth Inhibition Studies: Immunocompromised female mice were implanted with tumor fragments from Champions TumorGraft PDX models (CTG-0192, CTG-0464). When average tumor volumes reached 150-300 mm³, mice were assigned to vehicle control or PF-06873600 (30 mg/kg) groups (n=5) and dosed orally twice daily (BID). Tumor volumes and body weights were measured regularly. The study continued until the mean tumor volume of the control group reached 1500 mm³ or day 60. [1] |
| ADME/Pharmacokinetics |
PF-06873600 is a neutral molecule with the following physicochemical properties: molecular weight = 471.5, SFlogD at pH 7.4 = 1.9, total polar surface area = 126, hydrogen bond donors = 2, hydrogen bond acceptors = 5, and solubility at pH 7.4 = 265 μM. In in vitro assays using low efflux cell lines, this compound exhibited high passive permeability (AB ~14 × 10⁻⁶ cm/s). In mice: plasma clearance (CLp) = 63 mL/min/kg, volume of distribution (Vss) = 0.9 L/kg, oral bioavailability (F) = 13%. In dogs: CLp = 8.4 mL/min/kg, Vss = 1.1 L/kg, F = 59%.
The time required to reach the maximum plasma concentration was 0.25 hours in mice and 1 hour in dogs. It had a high absorption rate (approximately 1.0 for mice and 0.8 for dogs). The human liver microsomal (HLM) clearance (Clint, app) of PF-06873600 was < 10.8 μL/min/mg. [1] |
| References | |
| Additional Infomation |
Ebvaciclib is an orally bioavailable cyclin-dependent kinase (CDK) inhibitor with potential antitumor activity. After administration, Ebvaciclib selectively targets, binds to, and inhibits CDK activity. Inhibition of these kinases leads to cell cycle arrest, induces apoptosis, and inhibits tumor cell proliferation. CDKs are ATP-dependent serine/threonine kinases and are important regulators of cell cycle progression and proliferation, frequently overexpressed in tumor cells. PF-06873600 is a potent and selective CDK2, CDK4, and CDK6 inhibitor, discovered through structure-based drug design and Free-Wilson analysis. It was designed to overcome potential resistance to selective CDK4/6 inhibitors by simultaneously targeting CDK2, which acts as a compensatory mechanism. The compound contains a (1R,2R)-2-hydroxy-2-methylcyclopentyl group, which molecular dynamics simulations indicate confers high lipophilicity and selectivity for CDK9. PF-06873600 entered Phase I clinical trials in 2018 for the treatment of cancer. [1]
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| Molecular Formula |
C20H27F2N5O4S
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|---|---|
| Molecular Weight |
471.521290063858
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| Exact Mass |
471.18
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| Elemental Analysis |
C, 53.99; H, 7.29; N, 13.69; O, 12.51; S, 12.53
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| CAS # |
2185857-97-8
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| Related CAS # |
PF-06873600 HCl;2185857-97-8;2185859-59-8 (SS-isomer);
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| PubChem CID |
134247638
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| Appearance |
White to light yellow solid powder
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| LogP |
1.4
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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 |
5
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| Heavy Atom Count |
32
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| Complexity |
859
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| Defined Atom Stereocenter Count |
2
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| SMILES |
C[C@]1(CCC[C@H]1N2C3=NC(=NC=C3C=C(C2=O)C(F)F)NC4CCN(CC4)S(=O)(=O)C)O
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| InChi Key |
QIEKHLDZKRQLLN-FOIQADDNSA-N
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| InChi Code |
InChI=1S/C20H27F2N5O4S/c1-20(29)7-3-4-15(20)27-17-12(10-14(16(21)22)18(27)28)11-23-19(25-17)24-13-5-8-26(9-6-13)32(2,30)31/h10-11,13,15-16,29H,3-9H2,1-2H3,(H,23,24,25)/t15-,20-/m1/s1
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| Chemical Name |
6-(difluoromethyl)-8-[(1R,2R)-2-hydroxy-2-methylcyclopentyl]-2-[(1-methylsulfonylpiperidin-4-yl)amino]pyrido[2,3-d]pyrimidin-7-one
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| Synonyms |
PF06873600; Ebvaciclib; PF 06873600; PF-06873600
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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) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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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 | 2.1208 mL | 10.6040 mL | 21.2080 mL | |
| 5 mM | 0.4242 mL | 2.1208 mL | 4.2416 mL | |
| 10 mM | 0.2121 mL | 1.0604 mL | 2.1208 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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