Palbociclib (PD-0332991) HCl

Catalog No.S1116 Batch:S111613

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Technical Data

Formula

C24H29N7O2.HCl
Molecular Weight 483.99 CAS No. 827022-32-2
Solubility (25°C)* In vitro Water 24 mg/mL (49.58 mM)
DMSO 5 mg/mL (10.33 mM)
Ethanol Insoluble
* <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.
* Room temperature shipping (Stability testing shows this product can be shipped without any cooling measures.)

Preparing Stock Solutions

Biological Activity

Description Palbociclib (PD-0332991) HCl is a highly selective inhibitor of CDK4/6 with IC50 of 11 nM/16 nM in cell-free assays, respectively. It shows no activity against CDK1/2/5, EGFR, FGFR, PDGFR, InsR, etc. Phase 3.
Targets
CDK4/CyclinD3 [1]
(Cell-free assay)		 CDK4/CyclinD1 [1]
(Cell-free assay)		 CDK6/CyclinD2 [1]
(Cell-free assay)
9 nM 11 nM 15 nM
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 (from 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.

  • Dosages

    0-150 mg/kg

  • Administration

    Given by gavage

Customer Product Validation

Data from [Pharmacogenomics J, 2013, 13(1), 94-104]

Data from [Clin Transl Oncol, 2012, 14(3), 197-206 ]

Data from [Clin Cancer Res, 2011, 17(13), 4513-22]

, , Dr. Gao Zhang of University of Pennsylvania

Selleck's Palbociclib (PD-0332991) HCl has been cited by 467 publications

An intermediate Rb-E2F activity state safeguards proliferation commitment [ Nature, 2024, 631(8020):424-431] PubMed: 38926571
Defining the KRAS- and ERK-dependent transcriptome in KRAS-mutant cancers [ Science, 2024, 384(6700):eadk0775] PubMed: 38843331
Chronic stress increases metastasis via neutrophil-mediated changes to the microenvironment [ Cancer Cell, 2024, S1535-6108(24)00037-0] PubMed: 38402610
Cyclin-dependent kinase 4 drives cystic kidney disease in the absence of mTORC1 signaling activity [ Kidney Int, 2024, S0085-2538(24)00627-6] PubMed: 39218392
Reciprocal antagonism of PIN1-APC/CCDH1 governs mitotic protein stability and cell cycle entry [ Nat Commun, 2024, 15(1):3220] PubMed: 38622115
A renal clearable fluorogenic probe for in vivo β-galactosidase activity detection during aging and senolysis [ Nat Commun, 2024, 15(1):775] PubMed: 38278798
Comprehensive multi-omics analysis reveals WEE1 as a synergistic lethal target with hyperthermia through CDK1 super-activation [ Nat Commun, 2024, 15(1):2089] PubMed: 38453961
Proteomic analysis reveals a PLK1-dependent G2/M degradation program and a role for AKAP2 in coordinating the mitotic cytoskeleton [ Cell Rep, 2024, 43(8):114510] PubMed: 39018246
ERK hyperactivation serves as a unified mechanism of escape in intrinsic and acquired CDK4/6 inhibitor resistance in acral lentiginous melanoma [ Oncogene, 2024, 43(6):395-405] PubMed: 38066089
Intracellular calcium links milk stasis to lysosome-dependent cell death during early mammary gland involution [ Cell Mol Life Sci, 2024, 81(1):29] PubMed: 38212474

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