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Purity: ≥98%
Palbociclib Isethionate (formerly known as PD0332991; PD-0332991; Ibrance), the isethionate salt of Palbociclib, is an orally bioavailable pyridopyrimidine-based inhibitor of CDK4/6 with potential antitumor activity and was approved as an anticancer drug. In cell-free experiments, it inhibits CDK4/6 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 |
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 |
PD 0332991 shows complete CDK4/6 selectivity and negligible or no activity against other CDKs. With an IC50 of 66 nM and 63 nM, respectively, PD 0332991 effectively lowers Rb phosphorylation at Ser780 and Ser795 in MDA-MB-435 breast cancer cells. By keeping cells from going into S phase, PD 0332991 suppresses DNA replication and is a strong inhibitor of cell growth. With IC50 values ranging from 0.04-0.17 μM, PD 0332991 inhibits thymidine incorporation into the DNA of Rb-positive human breast (including MDA-MB-435, MCF-7), colon (H1299), and lung carcinomas (Colo-205) as well as human leukemias (CRRF-CEM and K562). In the G1 period, PD 0332991 significantly raises the percentage of MDA-MB-453.[1] In cycling CD138+ primary bone marrow myeloma cells, nontransformed primary B cells, MM1.S, and CAG HMCLs cell line, PD 0332991 inhibits phosphorylation of Rb with an IC50 of <0.1 μM, 0.05 μM, and 60-70 nM, respectively. Moreover, CD138+ primary bone marrow myeloma and nontransformed primary B cells undergo G1 arrest when treated with PD 0332991. With a ~0.05 μM IC50, PD 0332991 causes G1 arrest in MM1.S.[2] PD 0332991 specifically inhibits the growth of human breast cancer cell lines that are positive for the luminal estrogen receptor (HER2-positive included). In most sensitive lines, PD 0332991 raises the expression of the pRb and cyclin D1 genes while lowering that of CDKN2A (p16). In cell lines with conditioned resistance to ER blockade, PD 0332991 increases sensitivity to tamoxifen.[3]
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| ln Vivo |
PD 0332991 (150 mg/kg) causes a corresponding delay in tumor growth and rapid regressions in Colo-205 colon carcinoma xenografts. In MDA-MB-435 breast cancer, PD 0332991 (150 mg/kg) causes total tumor stasis and cell death. In mice with SF-295 glioblastoma xenografts, as well as in ZR-75-1 breast and PC-3 prostate tumor models, PD 0332991 (150 mg/kg) also causes a significant tumor regression (complete suppression of tumor growth). Over the course of a full 24-hour period, PD 0332991 (150 mg/kg) suppresses Rb Ser780 phosphorylation in MDA-MB-435 breast carcinoma. In Colo-205 carcinoma xenografts, PD 0332991 (150 mg/kg) down-regulates expression of four E2F-regulated genes: CDC2, CCNE2, TK1, and TOP2A.[1] Moreover, PD 0332991 quickly stops the growth of myeloma tumors.[2]
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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 24-well plates, cells are seeded in duplicate, with 5,000–10,000 cells per well. PD 0332991 is added in various concentrations the day following plating. Drug-free control wells are also seeded. Following incubation, trypsinized cells are added to isotone solution, counted right away using a Coulter Z2 particle counter.
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| Animal Protocol |
Human colon carcinoma xenografts Colo-205
150 mg/kg o.p. injection every day |
| References |
| Molecular Formula |
C26H35N7O6S
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| Molecular Weight |
573.66
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| Exact Mass |
573.23695304
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| Elemental Analysis |
C, 54.44; H, 6.15; N, 17.09; O, 16.73; S, 5.59
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| CAS # |
827022-33-3
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| Related CAS # |
Palbociclib;571190-30-2;Palbociclib monohydrochloride;827022-32-2;Palbociclib dihydrochloride
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| Appearance |
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.C(CS(=O)(=O)O)O
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| InChi Key |
LYYVFHRFIJKPOV-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C24H29N7O2.C2H6O4S/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;3-1-2-7(4,5)6/h7-8,13-14,17,25H,3-6,9-12H2,1-2H3,(H,26,27,28,29);3H,1-2H2,(H,4,5,6)
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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;2-hydroxyethanesulfonic acid
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| Synonyms |
PD0332991 isethionate salt; PD-0332991; PD 0332991; Palbociclib isethionate salt; 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: ≥ 1 mg/mL (1.74 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 10.0 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. Solubility in Formulation 2: Saline: 30 mg/mL (add these co-solvents sequentially from left to right, and one by one). Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.7432 mL | 8.7160 mL | 17.4319 mL | |
| 5 mM | 0.3486 mL | 1.7432 mL | 3.4864 mL | |
| 10 mM | 0.1743 mL | 0.8716 mL | 1.7432 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 |
| NCT04693468 | Recruiting | Drug: Palbociclib Isethionate Drug: Crizotinib |
Advanced Malignant Solid Neoplasm Metastatic Malignant Solid Neoplasm |
M.D. Anderson Cancer Center | December 1, 2020 | Phase 1 |
| NCT01602887 | Completed | Drug: PD-0332991 | Healthy | Pfizer | May 2012 | Phase 1 |
| NCT02041273 | Completed | Drug: palbociclib isethionate (phase 1 and 2 studies) Drug: palbociclib commercial free base capsule |
Healthy | Pfizer | January 2014 | 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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