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Purity: =99.8%
Palbociclib HCl (Pfizer trade name Ibrance, also known as PD-0332991), the HCl salt of Palbociclib, is a highly selective, orally bioavailable pyridopyrimidine-derived inhibitor of CDK4/6 with potential antineoplastic activity. In cell-free experiments, it inhibits CDK4 and CDK6 with IC50s of 11 nM and 16 nM, respectively. Many tumor cells overexpress CDK4 and CDK6, and Pfizer's palbociclib is the first CDK4/6 inhibitor to be approved by the FDA as a cancer treatment in 2017. There is no evidence of any activity against PDGFR, EGFR, FGFR, CDK1/2/5, InsR, etc. In vitro, it is a strong anti-proliferative agent that induces an exclusive G1 arrest in Rb-positive tumor cells. It has been shown to cause G1 arrest in primary bone marrow cells and stop tumor growth in disseminated human myeloma xenografts.
| Targets |
DYRK1A (IC50 = 2000 nM); MAPK (IC50 = 8000 nM); Cdk4/cyclin D3 (IC50 = 9 nM); Cdk4/cyclin D1 (IC50 = 11 nM); Cdk6/cyclin D2 (IC50 = 16 nM)
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| ln Vitro |
PD 0332991 has minimal impact on FGFR, PGFR, IR, EGFR, and other protein kinases. PD 0332991 is a Cdk4 non-ATP competitive inhibitor. Because of lowered Rb phosphorylation at Ser780, PD 0332991 inhibits MDA-MB-435 breast carcinoma cells with an IC50 of 66 nM. With IC50 values ranging from 0.04-0.17 μM, PD 0332991 inhibits the thymidine incorporation into the DNA of human leukemias and Rb-positive breast, colon, and lung carcinomas. Rb-negative cells exhibit no activity for PD 0332991. MDA-MB-453 breast and Colo-205 carcinoma cells accumulate cells in G1 in response to PD 0332991. Additionally, PD 0332991 exhibits activity in the immunocompetent model of 5T33MM myeloma cells, making the cells more susceptible to bortezomib-induced cell death.[2] PD 0332991 suppresses MDA-MB-175, ZR-75-30, CAMA-1, MDA-MB-134, HCC-202, and UACC-893, among other luminal ER-positive and HER2-amplified breast cancer cell lines. In these cell lines, PD 0332991 increases the effectiveness of trastuzumab and tamoxifen. In the tamoxifen-resistant MCF7 cells, PD 0332991 increases the sensitivity of tamoxifen.[3] A recent study demonstrates that malignant rhabdoid tumor (MRT) cell lines, such as MP-MRT-AN, KP-MRT-RY, G401, and KP-MRT-NS, can be suppressed by PD 0332991, and that the MRT cell lines' susceptibility to PD 0332991 is inversely connected with p16 expression.[4]
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| ln Vivo |
PD 0332991 shows total tumor stasis in an MDA-MB-435 xenograft at 150 mg/kg. Additionally, PD 0332991 exhibits broad-spectrum antitumor activity in multiple human tumor xenografts through the down-regulation of genes under the transcriptional control of E2F and the removal of phospho-Rb and the proliferative marker Ki-67 from tumor tissue. [1]
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| Enzyme Assay |
CDK assays are run in 96-well filter plates for kinetic analysis and IC50 calculations. By infecting insect cells with baculovirus, all CDK-cyclin kinase complexes are expressed and purified. A portion of pRb fused to GST (amino acids 792–928) serves as the substrate for the assays (GST•RB-Cterm). 20 mM Tris-HCl, pH 7.4, 50 mM NaCl, 1 mM dithiothreitol, 10 mM MgCl2, 25 μM ATP (for CDK4-cyclin D1, CDK6-cyclin D2, and CDK6-cyclin D3), 0.25 μCi of [γ-32P]ATP, 20 ng of enzyme, 1 μg of GST•RB-Cterm, and suitable dilutions of inhibitor are included in the overall reaction volume of 0.1 mL. After adding all the ingredients to the wells—aside from the [γ-32P]ATP—they are put on a plate mixer for two minutes. Addition of [γ-32P]ATP initiates the reaction, which is then incubated for 15 minutes at 25°C. In order to allow the substrate to precipitate, the reaction is stopped by adding 0.1 mL of 20% trichloroacetic acid and keeping the plate at 4°C for at least an hour. After five well washes with 0.2 mL of 10% trichloroacetic acid, radioactive incorporation is measured using a β plate counter.
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| Cell Assay |
In a 96-well plate, 2 × 104 cells are seeded per well and incubated for a full night. After being added to the wells, PD 0332991 (0.01-1 μM) is incubated for an additional 24 hours at 37 °C. [14C]Thymidine (0.1 μCi) is added to each well and incorporation of the radiolabel is allowed to proceed for 72 hours. Using a β plate counter, one can determine the incorporerated radioactivity.
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| Animal Protocol |
Advanced stage human tumor xenografts including Colo-205, MDA-MB-435 breast, SF-295 glioblastoma, ZR-75-1 breast, PC-3 prostate, H125 lung, SW-620 colon, H23 lung and MDA-MB-468 breast (Rb negative) are established in severe combined immunodeficient mice.
0-150 mg/kg Given by gavage |
| References |
| Molecular Formula |
C24H29N7O2.HCL
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|---|---|
| Molecular Weight |
483.99
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| Exact Mass |
483.2149509
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| Elemental Analysis |
C, 59.56; H, 6.25; Cl, 7.33; N, 20.26; O, 6.61
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| CAS # |
827022-32-2
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| Related CAS # |
Palbociclib;571190-30-2;Palbociclib hydrochloride;571189-11-2;Palbociclib-d8;1628752-83-9;Palbociclib isethionate;827022-33-3;Palbociclib dihydrochloride;Palbociclib orotate;2757498-64-7
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| Appearance |
Yellow solid powder
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| SMILES |
CC1=C(C(=O)N(C2=NC(=NC=C12)NC3=NC=C(C=C3)N4CCNCC4)C5CCCC5)C(=O)C.Cl
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| InChi Key |
STEQOHNDWONVIF-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C24H29N7O2.ClH/c1-15-19-14-27-24(28-20-8-7-18(13-26-20)30-11-9-25-10-12-30)29-22(19)31(17-5-3-4-6-17)23(33)21(15)16(2)32;/h7-8,13-14,17,25H,3-6,9-12H2,1-2H3,(H,26,27,28,29);1H
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| Chemical Name |
6-acetyl-8-cyclopentyl-5-methyl-2-[(5-piperazin-1-ylpyridin-2-yl)amino]pyrido[2,3-d]pyrimidin-7-one;hydrochloride
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| Synonyms |
Palbociclib; PD-332991; PD332991; PD 332991; PD0332991; PD-0332991; PD0332991 HCl, PD-0332991 hydrochloride; PD 0332991; Palbociclib HCl; Trade name: Ibrance
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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) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 0.54 mg/mL (1.12 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 5.4 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 0.54 mg/mL (1.12 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 5.4 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. 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. View More
Solubility in Formulation 3: Saline: 20 mg/mL Solubility in Formulation 4: 20 mg/mL (41.32 mM) in 0.5%HPMC 1%Tween80 (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication. Solubility in Formulation 5: 4.17 mg/mL (8.62 mM) in Lactic acid buffer (50 mM, pH 4.0) (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.0662 mL | 10.3308 mL | 20.6616 mL | |
| 5 mM | 0.4132 mL | 2.0662 mL | 4.1323 mL | |
| 10 mM | 0.2066 mL | 1.0331 mL | 2.0662 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 |
| NCT06003114 | Active Recruiting |
Drug: Palbociclib | Breast Cancer | Pfizer | September 2015 | |
| NCT03936270 | Active Recruiting |
Drug: Palbociclib 125mg Drug: Letrozole 2.5mg |
Ovarian Cancer | Latin American Cooperative Oncology Group |
January 27, 2020 | Phase 2 |
| NCT02738866 | Active Recruiting |
Drug: Palbociclib Drug: Fulvestrant |
Metastatic Breast Cancer | Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins |
October 25, 2016 | Phase 2 |
| NCT05069038 | Recruiting | Drug: Palbociclib 125mg | Breast Cancer | University of Nebraska | March 2, 2022 | Phase 2 |
| NCT04360941 | Recruiting | Drug: Palbociclib Drug: Avelumab |
ER+ Breast Cancer Recurrent Breast Cancer |
Royal Marsden NHS Foundation Trust |
August 11, 2020 | Phase 1 |
 Evaluation of IC50concentrations of the CDK inhibitors dinaciclib and palbociclib on proliferation, and their effects on CDK-Rb-E2F signaling in human HPASMCs from healthy donors and IPAH patients.Nat Commun.2019May 17;10(1):2204. |
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 Effects of the CDK inhibitors dinaciclib and palbociclib on proliferation, cell cycle, and apoptosis.Nat Commun.2019May 17;10(1):2204. |
 Effects of palbociclib on disease progression in the MCT rat model of pulmonary arterial hypertension.Nat Commun.2019May 17;10(1):2204. |
 Effects of palbociclib on disease progression in the Su/Hox rat model of pulmonary arterial hypertension.Nat Commun.2019May 17;10(1):2204. |
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 Ex vivo analyses of lung tissue for reversal of remodeling and in vivo drug efficacy in the Su/Hox model.Nat Commun.2019May 17;10(1):2204. |
 Proposed mechanism of action of palbociclib and dinaciclib in PAH. Multiple growth factors, cytokines, and mitogens induce the activation of cyclin-dependent kinases (CDKs), e.g., by increasing the expression of cyclin D1.Nat Commun.2019May 17;10(1):2204. |
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