| Size | Price | Stock | Qty |
|---|---|---|---|
| 10mg |
|
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| 100mg | |||
| 500mg |
Purity: ≥98%
| Targets |
CDK6
Palbociclib-propargyl targets the cyclin-dependent kinase 6 (CDK6). It is a ligand that binds to CDK6, serving as the targeting moiety in PROTAC molecules. By linking to an E3 ligase ligand (such as CRBN ligand) via a PEG linker, the resulting PROTAC recruits an E3 ubiquitin ligase to CDK6, leading to its ubiquitination and subsequent degradation by the proteasome. |
|---|---|
| ln Vitro |
A focused PROTAC library hijacking cancer therapeutic target CDK6 was developed. A design principle as "match/mismatch" was proposed for understanding the degradation profile differences in these PROTACs. Notably, potent PROTACs with specific and remarkable CDK6 degradation potential were generated by linking CDK6 inhibitor palbociclib and E3 ligase CRBN recruiter pomalidomide. The PROTAC strongly inhibited proliferation of hematopoietic cancer cells including multiple myeloma and robustly degraded copy-amplified/mutated forms of CDK6, indicating future potential clinical applications.[1]
Palbociclib-propargyl itself is a ligand for CDK6 and does not have intrinsic inhibitory activity in the same way as the parent compound palbociclib. Its activity is measured by its ability to form functional PROTACs. The PROTAC CP-10, which incorporates palbociclib-propargyl, shows a DC50 of 2.1 nM for degrading CDK6. This demonstrates the potent activity of the palbociclib-propargyl-based PROTAC. |
| ln Vivo |
The in vivo activity of palbociclib-propargyl is evaluated through the PROTAC molecules that incorporate it. The PROTAC CP-10, which uses palbociclib-propargyl as the CDK6 ligand, has been shown to degrade CDK6 with a DC50 of 2.1 nM. While specific in vivo data for palbociclib-propargyl itself is not available, the PROTACs incorporating it are expected to have in vivo activity in degrading CDK6 and inhibiting tumor growth.
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| Enzyme Assay |
In vitro kinase assay indicated that the kinase inhibitory activity of CP-10 for CDK4 or CDK6 was 10–25 fold weaker than that of PD, implying the compromised binding affinity between CP-10 for CDK4 or CDK6 (Fig. S4C). Difference in endogenous abundance for both could be ruled out since FLAG-tagged CDK6 was degraded with greater percentage than FLAG-tagged CDK4 when they were expressed at the same level (Fig. S4D). The selectivity could be partially explained by the more stable complex formed by CP-10 and CDK6 than CDK4, or more “match” as displayed by the docking simulation (Fig. 3E). The fact that CDK4 has less lysine residues (11 in CDK4 vs 18 in CDK6) for ubiquitination may also contribute to the selectivity, which awaits further exploration. Nonetheless, preferred degradation of CDK6 over CDK4 indicates that PROTAC CP-10 is in a better match for CDK6 than CDK4, via proper linker and favorable orientation. A stable and “matched” ternary complex of target, E3 ligase and PROTAC could be formed despite attenuated target-binding affinity[1].
The binding of palbociclib-propargyl to CDK6 is typically assessed using biochemical binding assays. These assays measure the affinity of the ligand for the target protein, often using surface plasmon resonance (SPR) or isothermal titration calorimetry (ITC). Alternatively, competition binding assays with a labeled reference compound can be used to determine the binding affinity. |
| Cell Assay |
Cell-based assays are used to evaluate the activity of PROTACs incorporating palbociclib-propargyl. Cells are treated with the PROTAC, and the degradation of CDK6 protein is measured by Western blot or ELISA. The DC50 (the concentration at which 50% of the target protein is degraded) is calculated from dose-response curves. The functional consequences of CDK6 degradation, such as inhibition of cell proliferation, can also be assessed.
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| Animal Protocol |
Palbociclib-propargyl is typically used in vitro to synthesize PROTAC molecules. The resulting PROTACs are then evaluated in vivo in animal models. In these studies, the PROTAC is administered to tumor-bearing mice, and its effects on CDK6 levels, tumor growth inhibition, and pharmacokinetic properties are assessed. However, specific protocols for palbociclib-propargyl itself are not available.
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| ADME/Pharmacokinetics |
Palbociclib-propargyl has a molecular weight of 485.58 and a molecular formula of C27H31N7O2. Purity is typically >98%. The compound appears as a solid. Storage of the powder is recommended at -20°C for up to 3 years; in solvent at -20°C for up to 6 months. It is soluble in DMSO. The compound is a PROTAC ligand targeting CDK6.
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| Toxicity/Toxicokinetics |
Palbociclib-propargyl is a research compound and its full toxicological profile is not detailed in the available literature. As a ligand used in PROTAC synthesis, its toxicity would be evaluated as part of the overall safety profile of the resulting PROTAC molecules. Standard safety precautions should be followed when handling the compound.
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| References | |
| Additional Infomation |
In summary, we constructed a focused library of CDK6 degraders and systematically evaluated factors such as linker length, spatial orientation, and binding affinity to help understand the match/mismatch between PROTACs and targets and to infer optimal strategies for future CDK6 degradation design or optimization. Notably, we found that: i) pomalidomide-based PROTACs recruit CRBN rather than the E3 ligases tested elsewhere, resulting in functional degraders; ii) our application of the CDK4/CDK6 dual ligand palbociclib unexpectedly yielded CDK6-selective PROTACs; iii) the representative palbociclib-derived PROTAC CP-10 exhibited remarkable potency in inhibiting the proliferation of various hematopoietic cancer cells, including multiple myeloma; and iv) mutated and overexpressed CDK6 could still be degraded by CP-10. These data further confirm the growing trend of potential clinical benefits of PROTAC technology and also demonstrate the specific applications of CDK6 degradation in certain cancers.
Palbociclib-propargyl (CAS#: 2366269-23-8) is a ligand for CDK6 used in the synthesis of PROTACs, connecting to the CRBN ligand through a PEG linker to form PROTAC CP-10. CP-10 shows a DC50 of 2.1 nM for degrading CDK6. Palbociclib-propargyl is a valuable research tool for targeted protein degradation in cancer biology, enabling the study of CDK6 function and the development of novel cancer therapeutics. |
| Molecular Formula |
C27H31N7O2
|
|---|---|
| Molecular Weight |
485.580744981766
|
| Exact Mass |
485.253
|
| CAS # |
2366269-23-8
|
| PubChem CID |
139600348
|
| Appearance |
Typically exists as Light yellow to yellow solids at room temperature
|
| LogP |
2.4
|
| Hydrogen Bond Donor Count |
1
|
| Hydrogen Bond Acceptor Count |
8
|
| Rotatable Bond Count |
6
|
| Heavy Atom Count |
36
|
| Complexity |
912
|
| Defined Atom Stereocenter Count |
0
|
| SMILES |
CC1=C(C(=O)N(C2=NC(=NC=C12)NC3=NC=C(C=C3)N4CCN(CC4)CC#C)C5CCCC5)C(=O)C
|
| InChi Key |
SLFZXPQZLOODKL-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C27H31N7O2/c1-4-11-32-12-14-33(15-13-32)21-9-10-23(28-16-21)30-27-29-17-22-18(2)24(19(3)35)26(36)34(25(22)31-27)20-7-5-6-8-20/h1,9-10,16-17,20H,5-8,11-15H2,2-3H3,(H,28,29,30,31)
|
| Chemical Name |
6-acetyl-8-cyclopentyl-5-methyl-2-[[5-(4-prop-2-ynylpiperazin-1-yl)pyridin-2-yl]amino]pyrido[2,3-d]pyrimidin-7-one
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| Synonyms |
Palbociclib-propargyl; 2366269-23-8; PROTAC CDK6 ligand 1; AKOS040743750; MS-29025;
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| 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 Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), 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) |
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 | 2.0594 mL | 10.2970 mL | 20.5939 mL | |
| 5 mM | 0.4119 mL | 2.0594 mL | 4.1188 mL | |
| 10 mM | 0.2059 mL | 1.0297 mL | 2.0594 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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