Palbociclib (PD-0332991) HCl Licensed by Pfizer

Palbociclib (PD-0332991) HCl is a highly selective inhibitor of CDK4/6 with IC50 of 11 nM/16 nM respectively. It shows no activity against CDK1/2/5, EGFR, FGFR, PDGFR, InsR, etc. Phase 3.

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Palbociclib (PD-0332991) HCl Chemical Structure

Palbociclib (PD-0332991) HCl Chemical Structure
Molecular Weight: 483.99

Validation & Quality Control

Customer Reviews(7)

Quality Control & MSDS

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Product Description

Biological Activity

Description Palbociclib (PD-0332991) HCl is a highly selective inhibitor of CDK4/6 with IC50 of 11 nM/16 nM respectively. It shows no activity against CDK1/2/5, EGFR, FGFR, PDGFR, InsR, etc. Phase 3.
Targets CDK4/CyclinD3 [1] CDK4/CyclinD1 [1] CDK6/CyclinD2 [1] CDK2/CyclinE2 [1] CDK2/CyclinA [1]

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IC50 9 nM 11 nM 15 nM >10 μM >10 μM
In vitro PD 0332991 has little effect on other protein kinases including EGFR, FGFR, PGFR, IR. PD 0332991 is a non-ATP competitive inhibitor of Cdk4. PD 0332991 inhibits MDA-MB-435 breast carcinoma cells with IC50 of 66 nM, which is due to reduced Rb phosphorylation at Ser780. PD 0332991 inhibits thymidine incorporation into the DNA of Rb-positive human breast, colon, and lung carcinomas as well as human leukemias, with IC50 values ranging from 0.04-0.17 μM. PD 0332991 shows no activity in Rb-negative cells. PD 0332991 causes an accumulation of cells in G1 in MDA-MB-453 breast and Colo-205 carcinoma cells. [1] PD 0332991 also shows activity in 5T33MM myeloma cells (immunocompetent model) and sensitizes the cells to killing by bortezomib. [2] PD 0332991 inhibits luminal ER-positive as well as HER2-amplified breast cancer cell lines including MDA-MB-175, ZR-75-30, CAMA-1, MDA-MB-134, HCC-202 and UACC-893. PD 0332991 enhances the activity of tamoxifen and trastuzumab in these cell lines. PD 0332991 enhances the sensitivity of tamoxifen in the MCF7 tamoxifen-resistant cells. [3] A recent study shows that PD 0332991 could suppress malignant rhabdoid tumor (MRT) cell lines including MP-MRT-AN, KP-MRT-RY, G401, KP-MRT-NS and the sensitivity of the MRT cell lines to PD 0332991 is inversely correlated with expression of p16. [4]
In vivo PD 0332991 indicates complete tumor stasis in a MDA-MB-435 xenograft at 150 mg/kg. PD 0332991 also shows broad-spectrum antitumor activity in multiple human tumor xenografts by eliminating phospho-Rb and the proliferative marker Ki-67 from tumor tissue and down-regulation of genes under the transcriptional control of E2F. [1]
Features Non-cytotoxic, and halts cancer cell growth & could be used in glioblastoma that has relapsed after temozolomide treatment (a chemotherapeutic used to treat many cancers).

Protocol(Only for Reference)

Kinase Assay: [1]

Cdk Assays A stock solution of PD0332991 is prepared in DMSO. CDK assays are performed in 96-well filter plates. All CDK-cyclin kinase complexes are expressed in insect cells through baculovirus infection and purified. The substrate for the assays is a fragment (amino acids 792–928) of pRb fused to GST (GST·RB-Cterm). The total volume in each well is 0.1 mL containing a final concentration of 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) containing 0.25 μCi of [γ-32P]ATP, 20 ng of enzyme, 1 μg of GST·RB-Cterm, and PD 0332991 (0.001-0.1μM). All components except the [γ-32P]ATP are added to the wells, and the plate is placed on a plate mixer for 2 min. The reaction is started by adding the [γ-32P]ATP and the plate is incubated at 25 °C for 15 min. The reaction is terminated by addition of 0.1 mL of 20% trichloroacetic acid and the plate is kept at 4  °C for at least 1 hour to allow the substrate to precipitate. The wells are then washed 5 times with 0.2 mL of 10% trichloroacetic acid and radioactive incorporation is determined with a β plate counter.

Cell Assay: [1]

Cell lines Tumor cell lines including MDA-MB-435, ZR-75-1, T-47D, MCF-7, H1299, Colo-205, MDA-MB-468, H2009, CRRF-CEM and K562
Concentrations 0.01-1 μM
Incubation Time 24 hours
Method Cells are seeded at 2 × 104 per well in a 96-well plate and incubated overnight. PD 0332991 (0.01-1 μM) is added to the wells and incubated at 37 °C for another 24 hours. [14C]Thymidine (0.1 μCi) is added to each well and incorporation of the radiolabel is allowed to proceed for 72 hours. Incorporated radioactivity is determined with a β plate counter.

Animal Study: [1]

Animal Models 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.
Formulation Dissolved in sodium lactate buffer (50 mM, pH 4.0)
Dosages 0-150 mg/kg
Administration Given by gavage
Solubility Saline, 20 mg/mL
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesBaboonDogMonkeyRabbitGuinea pigRatHamsterMouse
Weight (kg)121031.80.40.150.080.02
Body Surface Area (m2)0.60.50.240.150.050.0250.020.007
Km factor202012128653
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

References

[1] Fry DW, et al. Mol Cancer Ther, 2004, 3(11), 1427-1438.

[2] Menu E, et al. Cancer Res, 2008, 68(14), 5519-5523.

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Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2014-10-16)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT02222441 Not yet recruiting Healthy Pfizer November 2014 Phase 1
NCT02255461 Not yet recruiting Childhood Choroid Plexus Tumor|Childhood Ependymoblastoma|Childhood Grade III Meningioma|Childhood High-grade Cerebellar Astrocytoma|Childhood High  ...more Childhood Choroid Plexus Tumor|Childhood Ependymoblastoma|Childhood Grade III Meningioma|Childhood High-grade Cerebellar Astrocytoma|Childhood High-grade Cerebral Astrocytoma|Childhood Medulloepithelioma|Recurrent Childhood Anaplastic Astrocytoma|Recurrent Childhood Anaplastic Oligoastrocytoma|Recurrent Childhood Anaplastic Oligodendroglioma|Recurrent Childhood Brain Stem Glioma|Recurrent Childhood Cerebellar Astrocytoma|Recurrent Childhood Cerebral Astrocytoma|Recurrent Childhood Giant Cell Glioblastoma|Recurrent Childhood Glioblastoma|Recurrent Childhood Gliomatosis Cerebri|Recurrent Childhood Gliosarcoma|Recurrent Childhood Medulloblastoma|Recurrent Childhood Pineoblastoma|Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor Pediatric Brain Tumor Consortium|National Cancer Institut  ...more Pediatric Brain Tumor Consortium|National Cancer Institute (NCI) October 2014 Phase 1
NCT02142868 Available Advanced Breast Cancer (Female) Pfizer August 2014 --
NCT02059213 Recruiting Prostate Cancer University of Michigan Cancer Center|University of Utah|V  ...more University of Michigan Cancer Center|University of Utah|Vanderbilt-Ingram Cancer Center|Dana-Farber Cancer Institute|Johns Hopkins University|Thomas Jefferson University June 2014 Phase 2
NCT02154490 Recruiting Recurrent Non-small Cell Lung Cancer|Squamous Cell Lung Cancer|Stage IIIB Non-small Cell Lung Cancer|Stage IV Non-small Cell Lung Cancer Southwest Oncology Group|National Cancer Institute (NCI) June 2014 Phase 2|Phase 3

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Chemical Information

Download Palbociclib (PD-0332991) HCl SDF
Molecular Weight (MW) 483.99
Formula

C24H29N7O2.HCl

CAS No. 827022-32-2
Storage 3 years -20℃Powder
6 months-80℃in DMSO
Synonyms
Solubility (25°C) * In vitro DMSO 3 mg/mL (6 mM)
Water 30 mg/mL (61 mM)
Ethanol <1 mg/mL (<1 mM)
In vivo Saline 20 mg/mL
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
Chemical Name 6-acetyl-8-cyclopentyl-5-methyl-2-(5-(piperazin-1-yl)pyridin-2-ylamino)pyrido[2,3-d]pyrimidin-7(8H)-one hydrochloride

Research Area

Customer Reviews (7)


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Rating
Source PNAS 2011 108, 8417. Palbociclib (PD-0332991) HCl purchased from Selleck
Method Fluorescent Microscopy and Confocal Imaging
Cell Lines Tg:Pomc-Pttg embryo, Pomc-eGFP embryo
Concentrations 50 μM
Incubation Time 18-48 h
Results Although flavopiridol retarded early embryonic development before corticotroph ontogeny occurred, in vivo treatment of zebrafish embryos with R-roscovitine, olomoucine, PD-0332991, and CAY10572 starting at 18 hpf caused no apparent growth defect by 40 hpf . Strikingly, R-roscovitine-treated embryos exhibited approximately 40% reduction in pituitary POMC-eGFP expression compared with controls. A modest, approximately 20%, reduction of POMC-eGFP expression was also observed in the olomoucine-treated group (1.0 ± 0.08 vs. 0.8 ± 0.07, mean ± SE; n = 7 for each group; P = 0.07), whereas PD-0332991 and CAY10572 caused no significant change in pituitary POMC-eGFP expression compared with controls.

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Rating
Source Clin Cancer Res 2011 17(13). Palbociclib (PD-0332991) HCl purchased from Selleck
Method Western Blot/Growth assay
Cell Lines OE33/OE19/Flo1A cells
Concentrations 125 nM
Incubation Time 1/3/21 day
Results PD-0332991 reduces expression of cyclinA in all 3 cell lines. PD-0332991 has no effect on the expression level of either total pRB or RB2 (p130) in EAC cells. PD-0332991 caused a significant reduction in colony formation in soft agar in all 3 cell lines tested, indicative of a reduction in anchorage independence.

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Rating
Source Pharmacogenomics J 2013 13, 94-104 . Palbociclib (PD-0332991) HCl purchased from Selleck
Method Immunofluorescence
Cell Lines Patient tumor cell
Concentrations 3 uM
Incubation Time
Results Tumor organoids treated with VPA/ PD0332991 or SAHA/PD0332991 exhibited reduced structural integrity and increased cellular scatter with increasing concentrations of the drugs.

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Rating
Source Clin Transl Oncol 2012 14, 197-206 . Palbociclib (PD-0332991) HCl purchased from Selleck
Method Immunofluorescence
Cell Lines Murine MSCs cells
Concentrations 2 uM
Incubation Time 24-48 h
Results We show that when cells are treated with PD332991 for 24–48 h there is a marked decrease in nuclear expression of cdk4 in PAX7- FKHR-expressing mMSCs. Further analysis by immunofluorescence showed that there is a minor upregulation in expression of MyoD1 in cells treated with cdk4 inhibitor for 48 h.

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Rating
Source Dr. Gao Zhang of University of Pennsylvania. Palbociclib (PD-0332991) HCl purchased from Selleck
Method Western blot
Cell Lines WM3734 melanoma cells
Concentrations 0.25-4 μM
Incubation Time 36 h
Results

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Rating
Source Dr. Sabine Paternot and Dr Pierre Roger of IRIBHM, ULB, Brussels. Palbociclib (PD-0332991) HCl purchased from Selleck
Method Western blot
Cell Lines T98G glioma cells
Concentrations 1 μM
Incubation Time
Results

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Rating
Source Dr. Kun-Wei Liu from University of Pittsburgh. Palbociclib (PD-0332991) HCl purchased from Selleck
Method IB analysis, Quantification of soft agar assays
Cell Lines LN319 cells
Concentrations
Incubation Time
Results

Product Citations (12)

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