Palbociclib Isethionate

Catalog No.S1579 Batch:S157906

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Technical Data

Formula

C24H29N7O2.C2H6O4S
Molecular Weight 573.66 CAS No. 827022-33-3
Solubility (25°C)* In vitro Water 100 mg/mL (174.31 mM)
DMSO Insoluble
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.)

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Biological Activity

Description Palbociclib Isethionate is a highly selective inhibitor of CDK4/6 with IC50 of 11 nM/16 nM in cell-free assays. 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 exhibits absolute selectivity for CDK4/6 with little or no activity against other CDKs. PD 0332991 is effective at reducing Rb phosphorylation at Ser780 and Ser795 in MDA-MB-435 breast carcinoma cells with IC50 of 66 nM and 63 nM, respectively. PD 0332991 is a potent inhibitor of cell growth and suppresses DNA replication by preventing cells from entering S phase. PD 0332991 inhibits thymidine incorporation into the DNA of Rb-positive human breast (such as MDA-MB-435, MCF-7), colon (H1299), and lung carcinomas (Colo-205) as well as human leukemias (CRRF-CEM and K562), with IC50 values ranging from 0.04-0.17 μM. PD 0332991 significant increases the percentage of MDA-MB-453 in G1 period. [1] PD 0332991 inhibits phosphorylation of Rb in cycling CD138+ primary bone marrow myeloma cells, nontransformed primary B cells, MM1.S and CAG HMCLs cells line with IC50 of <0.1 μM, 0.05 μM, and 60-70 nM, respectively. PD 0332991 treatment also induces G1 arrest of CD138+ primary bone marrow myeloma and nontransformed primary B cells. PD 0332991 induces G1 arrest in MM1.S with IC50 of ~0.05 μM. [2] PD 0332991 preferentially inhibits proliferation of luminal estrogen receptor-positive (including HER2-positive) human breast cancer cell lines. PD 0332991 increases gene expression of pRb and cyclin D1 and decreases gene expression of CDKN2A (p16) in most sensitive lines. PD 0332991 enhances sensitivity to tamoxifen in cell lines with conditioned resistance to ER blockade. [3]
In vivo PD 0332991(150 mg/kg) produces rapid Colo-205 colon carcinoma xenografts regressions and a corresponding tumor growth delay. PD 0332991 (150 mg/kg) induces complete tumor stasis and cell kill in MDA-MB-435 breast carcinoma. PD 0332991 (150 mg/kg) also induces significant tumor regression in mice bearing the SF-295 glioblastoma xenografts, and in ZR-75-1 breast and PC-3 prostate tumor models (complete suppression of tumor growth). PD 0332991 (150 mg/kg) suppresses Rb Ser780 phosphorylation in MDA-MB-435 breast carcinoma over the full 24-hour period. PD 0332991 (150 mg/kg) down-regulates expression of four E2F-regulated genes CDC2, CCNE2, TK1, and TOP2A in Colo-205 carcinoma xenografts. [1] PD 0332991 also rapidly inhibits myeloma tumor growth. [2]
Features The 1st specific inhibitor for CDK4/6 to show promise in multiple cancers.

Protocol (from reference)

Kinase Assay:[4]
  • CDK activity assays

    CDK assays for IC50 determinations and kinetic evaluation 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 reaction volume 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) containing 0.25 μCi of [γ-32P]ATP, 20 ng of enzyme, 1 μg of GST•RB-Cterm, and appropriate dilutions of inhibitor. All components except the [γ-32P]ATP are added to the wells, and placed on a plate mixer for 2 min. The reaction is started by adding the [γ-32P]ATP, and incubated at 25℃ for 15 min. The reaction is terminated by addition of 0.1 mL of 20% trichloroacetic acid, and the plate is kept at 4 ℃ for at least 1 hr to allow the substrate to precipitate. The wells are then washed five times with 0.2 mL of 10% trichloroacetic acid, and radioactive incorporation is determined with a β plate counter.

Cell Assay:[3]
  • Cell lines

    Human breast cancer cells MDA-MB-435

  • Concentrations

    2 μM

  • Incubation Time

    6 days

  • Method

    Cells are seeded in duplicate at 5,000 to 10,000 cells per well in 24-well plates. The day after plating, different concentrations of PD 0332991 are added. Control wells without drug are also seeded. At the end of incubation, cells are trypsinizated and placed in Isotone solution and counted immediately using a Coulter Z2 particle counter.
Animal Study:[1]
  • Animal Models

    Human colon carcinoma xenografts Colo-205

  • Dosages

    150 mg/kg

  • Administration

    o.p. injection every day

References

  • https://pubmed.ncbi.nlm.nih.gov/15542782/
  • https://pubmed.ncbi.nlm.nih.gov/16885367/
  • https://pubmed.ncbi.nlm.nih.gov/19874578/
  • https://pubmed.ncbi.nlm.nih.gov/11278443/

Customer Product Validation

HT29 cells were treated with DMSO control, 1 uM selumetinib (Sel) or 5 uM PD0332991 (991) for 24 or 48 h after which time cells were lysed, subjected to SDS/PAGE and immunoblotted with the indicated antibodies.

Data from [ Biochem J , 2014 , 459(3), 513-24 ]

<p>Potentiation of SFN-induced cytotoxicity by a panel of CDK inhibitors in MDA-MB-231 cells. The fraction of cells killed (Fa ±SEM) by SFN in the presence of DMSO (vehicle) or a fixed concentration (0.2 uM) of PD0332991. The fraction of cells killed by CDK inhibitors at a fixed concentration of 0.2 uM is shown for comparison [dashed lines; gray shading (±SEM)]. MDE-CI analysis of drug interactions in the upper panels. CIs as a function of SFN concentration are shown. Black, gray, and white bars denote synergistic (CI < 0.9), additive (CI = 0.9-1.1), or antagonistic interactions (CI > 1.1), respectively. Synergistic ratios and SFN-EC50 are indicated. Data are representative of two to three independent experiments.</p>

Data from [ Neoplasia , 2013 , 15(8), 939-51 ]

<p> </p> <p>Patient tumor cell sensitivity to combinatorial treatment with histone deacetylase (HDAC)/cyclin-dependent kinase (CDK) inhibitors in 3-D culture. The effect of each drug or drug combination was assessed by fluorescent dye to identify live (green) and dead cells (red). Cells from breast reduction patients were used as non-cancer control in the assay.</p>

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

Immunoblot analysis of PD0332991-induced senescence in MEL10 cells. Cells were treated with indicated concentrations of PD0332991 with or without 10 nM rapamycin. After 1 day, cells were lysed and immunoblotting was performed with the indicated antibodies.

Data from [ Cell Cycle , 2013 , 12(18), 3063-9 ]

Selleck's Palbociclib Isethionate has been cited by 297 publications

SLFN11-mediated ribosome biogenesis impairment induces TP53-independent apoptosis [ Mol Cell, 2025, S1097-2765(25)00042-5] PubMed: 39909041
A bedside-to-bench translational analysis of NF1 alterations and CDK4/6 inhibitor resistance in hormone receptor-positive metastatic breast cancer [ EBioMedicine, 2025, 118:105828] PubMed: 40578027
Effect of Tasurgratinib as an Orally Available FGFR1-3 Inhibitor on Resistance to a CDK4/6 Inhibitor and Endocrine Therapy in ER+/HER2- Breast Cancer Preclinical Models [ Cancers (Basel), 2025, 17(7)1084] PubMed: 40227585
Dual Inhibition of CDK4/6 and XPO1 Induces Senescence With Acquired Vulnerability to CRBN-Based PROTAC Drugs [ Gastroenterology, 2024, S0016-5085(24)00062-3] PubMed: 38262581
Inhibition of GPX4 enhances CDK4/6 inhibitor and endocrine therapy activity in breast cancer [ Nat Commun, 2024, 15(1):9550] PubMed: 39500869
CDK-independent role of D-type cyclins in regulating DNA mismatch repair [ Mol Cell, 2024, 84(7):1224-1242.e13] PubMed: 38458201
SLC7A11 protects luminal A breast cancer cells against ferroptosis induced by CDK4/6 inhibitors [ Redox Biol, 2024, 76:103304] PubMed: 39153252
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
Patient-derived rhabdomyosarcoma cells recapitulate the genetic and transcriptomic landscapes of primary tumors [ iScience, 2024, 27(10):110862] PubMed: 39319271
A live single-cell reporter system reveals drug-induced plasticity of a cancer stem cell-like population in cholangiocarcinoma [ Sci Rep, 2024, 14(1):22619] PubMed: 39349745

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