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    Palbociclib (PD0332991) Isethionate
    Palbociclib (PD0332991) Isethionate

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    This product is for research use only, not for human use. We do not sell to patients.
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    InvivoChem Cat #: V1557
    CAS #: 827022-33-3 Purity ≥98%

    Description: Palbociclib (Pfizer trade name Ibrance, also known as PD-0332991) Isethionate, the isethionate salt of Palbociclib, is a highly selective, orally bioavailable pyridopyrimidine-derived inhibitor of CDK4/6 with IC50 of 11 nM and 16 nM in cell-free assays respectively. CDK4 and CDK6 are overexpressed in many tumor cells, and palbociclib, developed by Pfizer, is the first CDK4/6 inhibitor approved by FDA in 2017 as a cancer therapeutic. It shows no activity against CDK1/2/5, EGFR, FGFR, PDGFR, InsR, etc. It is a potent anti-proliferative agent against Rb-positive tumor cells in vitro, subsequently inducing an exclusive G1 arrest. It has been reported to prevent tumor growth in disseminated human myeloma xenografts and induce G1 arrest in primary bone marrow cells.

    References: Mol Cancer Ther. 2004 Nov;3(11):1427-38; Cancer Res. 2006 Aug 1;66(15):7661-7;  2018 Apr 18;9(5):446. ;  2018 Apr 18. pii: e98359. doi: 10.15252/embj.201798359.

    Related CAS#:571190-30-2 (free base); 827022-33-3 (isethionate salt);  827022-32-2 (HCl); 1628752-83-9 (Palbociclib D8); 2366269-23-8 (Palbociclib-propargyl)

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    Molecular Weight (MW)573.66
    FormulaC24H29N7O2.C2H6O4S
    CAS No.827022-33-3 (isethionate salt); 
    Storage-20℃ for 3 years in powder form
    -80℃ for 2 years in solvent
    Solubility (In vitro)DMSO: <1 mg/mL
    Water: 50 mg/mL (87.2 mM)
    Ethanol:<1 mg/mL
    Solubility (In vivo)Saline: 30 mg/mL
    SynonymsPD0332991 isethionate salt,  PD-0332991; PD 0332991; Palbociclib isethionate salt, Trade name: Ibrance 


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    In Vitro

    In vitro activity: 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. 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. 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.


    Kinase Assay: 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: Cells (Human breast cancer cells MDA-MB-435) 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.

    In VivoPD 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. PD 0332991 also rapidly inhibits myeloma tumor growth.
    Animal modelHuman colon carcinoma xenografts Colo-205
    Formulation & DosageDissolved in solution in sodium lactate buffer (50 mM, pH 4.0); ~150 mg/kg; i.p. injection
    References

    Mol Cancer Ther. 2004 Nov;3(11):1427-38; Cancer Res. 2006 Aug 1;66(15):7661-7; Breast Cancer Res. 2009;11(5):R77. doi: 10.1186/bcr2419.


    These protocols are for reference only. InvivoChem does not independently validate these methods.

    Palbociclib (PD0332991) Isethionate


    Evaluation of IC50 concentrations 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.  2019 May 17;10(1):2204.

     Palbociclib (PD0332991) Isethionate


    Effects of the CDK inhibitors dinaciclib and palbociclib on proliferation, cell cycle, and apoptosis.  2019 May 17;10(1):2204.

     Palbociclib (PD0332991) Isethionate


    Effects of palbociclib on disease progression in the MCT rat model of pulmonary arterial hypertension.  2019 May 17;10(1):2204.

     Palbociclib (PD0332991) Isethionate


    Effects of palbociclib on disease progression in the Su/Hox rat model of pulmonary arterial hypertension.  2019 May 17;10(1):2204.

     Palbociclib (PD0332991) Isethionate


    Ex vivo analyses of lung tissue for reversal of remodeling and in vivo drug efficacy in the Su/Hox model.  2019 May 17;10(1):2204.

     Palbociclib (PD0332991) Isethionate


    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.  2019 May 17;10(1):2204.

     

    Palbociclib (PD0332991) Isethionate

     

    Palbociclib (PD0332991) Isethionate

     

    Palbociclib (PD0332991) Isethionate


    Palbociclib (PD0332991) Isethionate

    Effects of PD 0332991 on phosphorylation of retinoblastoma gene product. Breast Cancer Res. 2009;11(5):R77.


    Palbociclib (PD0332991) Isethionate

    PD 0332991 and tamoxifen in a tamoxifen-insensitive cell line. Breast Cancer Res. 2009;11(5):R77.


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