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Purity: =99.95%
Palbociclib (formerly PD-0332991; PD0332991; Pfizer trade name Ibrance) is a highly selective, orally bioavailable pyridopyrimidine-based CDK4/6 inhibitor that has been approved for cancer treatment. In cell-free experiments, it inhibits CDK4/6 with an IC50 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 |
Cdk4/cyclin D3 (IC50 = 9 nM); Cdk4/cyclin D1 (IC50 = 11 nM); Cdk6/cyclin D2 (IC50 = 16 nM); DYRK1A (IC50 = 2000 nM); MAPK (IC50 = 8000 nM)
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| ln Vitro |
Palbociclib is a CKD4/6 inhibitor, dramatically lowers the viability of HR+/HER2+ tumor cells when combined with fulvestrant and tucatinib.[2]
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| ln Vivo |
Palbociclib a CKD4/6 inhibitor, exhibits superior efficacy in suppressing tumor growth in vivo when combinates with tucatinib and fulvestrant.[2]
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| Enzyme Assay |
In DMSO, a stock solution of PD0332991 is made. CDK assays are run on filter plates with 96 wells. By infecting insect cells with baculovirus, all CDK-cyclin kinase complexes are expressed and purified. A portion of pRb fused to GST (GST·RB-Cterm) spanning amino acids 792–928 serves as the substrate for the assays. Each well has a total volume of 0.1 mL and contains the following final concentrations: 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), or 12 μM ATP (for CDK2-cyclin E, CDK2-cyclin A, and CDC2-cyclin B). This mixture also contains 0.25 μCi of [γ-32P]ATP, 20 ng of enzyme, 1 μg of GST·RB-Cterm, and PD 0332991 (0.001-0.1μM). The plate is placed on a plate mixer for two minutes after all ingredients—aside from the [γ-32P]ATP—are added to the wells. The plate is incubated at 25°C for 15 minutes after the addition of [γ-32P]ATP to initiate the reaction. The plate is kept at 4 °C for at least an hour to allow the substrate to precipitate before the reaction is stopped by adding 0.1 mL of 20% trichloroacetic acid. Next, 0.2 mL of 10% trichloroacetic acid is used to wash the wells five times, and a β plate counter is used to measure the radioactive incorporation.
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| Cell Assay |
Cell viability is assessed using the Cell Titer Glo assay following a 72-hour vehicle or medication treatment. Prior to fulvestrant treatment, cells are grown in conditions free of estrogen and estradiol is added to a final concentration of 10-8 M. For every cell line, the IC30 values for palbociclib, fulvestrant, and tucatinib are determined; the IC30 concentrations are then utilized in the ensuing studies.
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| Animal Protocol |
NCG mice injected with MDA-MB-361 cells
50mg/kg o.g. Oral administration of PD 0332991 to mice bearing the Colo-205 human colon carcinoma produces marked tumor regression. Therapeutic doses of PD 0332991 cause elimination of phospho-Rb and the proliferative marker Ki-67 in tumor tissue and down-regulation of genes under the transcriptional control of E2F. The results indicate that inhibition of Cdk4/6 alone is sufficient to cause tumor regression and a net reduction in tumor burden in some tumors.[1] |
| References | |
| Additional Infomation |
Palbociclib is a member of the class of pyridopyrimidines that is 2-{[5-(piperazin-1-yl)pyridin-2-yl]amino}pyrido[2,3-d]pyrimidin-7-one bearing additional methyl, acetyl and cyclopentyl substituents at positions 5, 6 and 8 respectively. It is used in combination with letrozole for the treatment of metastatic breast cancer. It has a role as an EC 2.7.11.22 (cyclin-dependent kinase) inhibitor and an antineoplastic agent. It is a pyridopyrimidine, an aminopyridine, a secondary amino compound, a member of piperidines, an aromatic ketone, a member of cyclopentanes and a tertiary amino compound.
Palbociclib is a piperazine pyridopyrimidine that acts in the cell cycle machinery. It is a second generation cyclin-dependent kinase inhibitor selected from a group of pyridopyrimidine compounds due to its favorable physical and pharmaceutical properties. Palbociclib was developed by Pfizer Inc after the discovery that identified the cyclin-dependent kinases as key regulators of cell growth. It was originally FDA approved on March 2015 for the treatment of HR-positive, HER2-negative advanced or metastatic breast cancer and its indications were updated in April 2019 to include male patients based on findings from postmarketing reports and electronic health records demonstrating safety and clinical efficacy. View More
Palbociclib is a Kinase Inhibitor. The mechanism of action of palbociclib is as a Kinase Inhibitor, and Cytochrome P450 3A Inhibitor.
Palbociclib is indicated in combination with [letrozole] as initial endocrine-based therapy for the treatment of human epidermal growth factor receptor type 2 (HER2)-negative and hormone receptor(HR)-positive tumors in adult patients with advanced/metastatic breast cancer. It is as well approved in combination with [fulvestrant] in patients with disease progression with prior endocrine therapy. In the official labeling, the use of palbociclib should be accompanied with either an aromatase inhibition, no restricted to letrozole, as initial endocrine-based therapy in postmenopausal women or in man. The breast cancer starts as a group of cancer cells that grow into and destroy the nearby breast tissue. This growth can spread into other parts of the body which is called metastasis. According to the location of the cancer cells, it can be categorized in ductal carcinoma and lobular carcinoma. However, other types of breast cancer include inflammatory breast cancer, Paget disease of the breast, triple negative breast cancer non-Hodgkin lymphoma and soft tissue sarcoma. In males, breast cancer is usually treated as the cases of postmenopausal women and almost all the cases are ductal carcinoma. Palbociclib is a unique cyclin-dependent kinase inhibitor that is used in combination with aromatase inhibitors in the treatment of postmenopausal women with metastatic breast cancer. Palbociclib is associated with transient and usually mild elevations in serum aminotransferase during therapy and to an unusual form of liver injury called pseudocirrhosis caused by shrinkage of tumor metastases in the liver combined with desmoplastic changes and vascular damage, that can be severe, progressive and even fatal. Due to its mechanism of action, palbociclib inhibits cell growth and suppresses DNA replication in retinoblastoma tumor suppressor gene (RB) proficient cancer cells. As expected, these RB cells present a significant increase in the proportion of cells in G1 state and the presence of palbociclib produces effective dephosphorylation of RB, reduce proliferation and induce senescence causing cell-cycle arrest. In vitro studies showed the potential for palbociclib to reduce cellular proliferation of estrogen receptor-positive breast cancer cell lines through the inhibition of the cell-cycle progression from G1 to S phase. In this study, it was demonstrated that the sensitivity of the cells significantly increased with the expression of _RB1_ and _CCND1_ and low expression of _CDKN2A_. As well, palbociclib, combined with antiestrogens, enhanced _in vivo_ antitumor activity in estrogen receptor-positive breast cancer mouse models. In clinical trials, palbociclib, in combination with letrozole, was shown to significantly increase the progression-free survival (PFS) in patients with metastatic breast cancer without prior endocrine treatment. In the results, the PFS increased from 4.5 to 9.5 months with an overall response rate (ORR) of 24.6%. Absorption Palbociclib presents a linear pharmacokinetic profile and its peak plasma concentration was observed 6-12 hours after oral administration. The oral bioavailability is reported to be of 46% with a steady-state reached after 8 days and a median accumulation ratio of 2.4. The absorption of palbociclib is significantly reduced under fasting conditions and hence, food intake is recommended when this drug is administered. Route of Elimination The main route of elimination of palbociclib is through feces after hepatic metabolism while renal clearance seems to play a minor role accounting only for 17.5% of the eliminated dose. Volume of Distribution The mean apparent distribution of palbociclib is 2583 L which suggests that palbociclib penetrates extensively into peripheral tissues. Clearance The mean apparent oral clearance of palbociclib is of 63.1 L/h. Metabolism / Metabolites Palbociclib is mainly hepatically transformed. the metabolism is mainly performed by the activities of the cytochrome P450 isoenzyme 3A and the sulfotransferase 2A1. The metabolism of palbociclib is represented mainly by reactions of oxidation and sulfonation followed by acylation and glucuronidation as minor reactions. After its metabolism, palbociclib forms mainly inactive glucuronide and sulfamic acid conjugates. The major circulating metabolite, accounting for 1.5% of the dose in excreta is is the glucuronide conjugate. Biological Half-Life The mean plasma elimination half-life of palbociclib is 29 hours. Mechanism of Action Palbociclib is a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor that acts by binding to the ATP pocket with an IC50 in the range of 9-15 nmol/L. It is important to consider that it presents low to absent activity against other kinases. The CDK4/6 kinase is involved, with coregulatory partner cyclin D, in the G1-S transition. Hence, inhibition of this step prevents cell cycle progression in cells in whose this pathway is functioning. This step includes the pathways of the phosphorylation of retinoblastoma protein and the E2F family of transcription factors. |
| Molecular Formula |
C24H29N7O2
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|---|---|
| Molecular Weight |
447.54
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| Exact Mass |
447.24
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| Elemental Analysis |
C, 64.41; H, 6.53; N, 21.91; O, 7.15
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| CAS # |
571190-30-2
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| Related CAS # |
Palbociclib monohydrochloride;827022-32-2;Palbociclib hydrochloride;571189-11-2;Palbociclib-d8;1628752-83-9;Palbociclib isethionate;827022-33-3;Palbociclib dihydrochloride;Palbociclib orotate;2757498-64-7;Palbociclib-d4 hydrochloride
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| PubChem CID |
5330286
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| Appearance |
Yellow solid powder
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| Density |
1.3±0.1 g/cm3
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| Boiling Point |
711.5±70.0 °C at 760 mmHg
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| Melting Point |
200ºC
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| Flash Point |
384.1±35.7 °C
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| Vapour Pressure |
0.0±2.3 mmHg at 25°C
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| Index of Refraction |
1.648
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| LogP |
0.99
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| tPSA |
105.04
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| SMILES |
CC1=C(C(=O)N(C2=NC(=NC=C12)NC3=NC=C(C=C3)N4CCNCC4)C5CCCC5)C(=O)C
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| InChi Key |
AHJRHEGDXFFMBM-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C24H29N7O2/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)
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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 |
PD0332991; Palbociclib free base; UNII-G9ZF61LE7G; 6-acetyl-8-cyclopentyl-5-methyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one; PD-0332991; PD 0332991; 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 Note: This product requires protection from light (avoid light exposure) during transportation and storage. |
| 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: ≥ 2 mg/mL (4.47 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 20.0 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: ≥ 2 mg/mL (4.47 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 20.0 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: 6.67 mg/mL (14.90 mM) in 0.5% CMC/saline water (add these co-solvents sequentially from left to right, and one by one), suspension solution; Need ultrasonic and warming and heat to 42°C. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2344 mL | 11.1722 mL | 22.3444 mL | |
| 5 mM | 0.4469 mL | 2.2344 mL | 4.4689 mL | |
| 10 mM | 0.2234 mL | 1.1172 mL | 2.2344 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 |
| NCT03936270 | Active Recruiting |
Drug: Palbociclib 125mg Drug: Letrozole 2.5mg |
Ovarian Cancer | Latin American Cooperative Oncology Group |
January 27, 2020 | Phase 2 |
| NCT04288089 | Active Recruiting |
Drug: Palbociclib (75, 100, 125 milligram [mg]) Drug: H3B-6545 (150, 300, 450 mg) |
Receptors, Estrogen Genes, Erbb-2 |
Eisai Inc. | April 1, 2020 | Phase 1 |
| NCT02738866 | Active Recruiting |
Drug: Palbociclib Drug: Fulvestrant |
Metastatic Breast Cancer | Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins |
October 25, 2016 | Phase 2 |
| NCT01864746 | Active Recruiting |
Drug: Palbociclib PD-0332991 Drug: Placebo |
Breast Cancer Her2-normal |
German Breast Group | November 2013 | Phase 3 |
| NCT03446157 | Active Recruiting |
Drug: Cetuximab Drug: Palbociclib |
Colonic Cancer Colon Cancer |
UNC Lineberger Comprehensive Cancer Center |
March 13, 2018 | Phase 2 |
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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