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PD 0332991 (Palbociclib) HCl

Catalog No.: GC17935

Palbociclib (PD 0332991) monohydrochloride is an orally active selective CDK4 and CDK6 inhibitor with IC50 values of 11 and 16 nM, respectively. PD 0332991 (Palbociclib) HCl has potent anti-proliferative activity and induces cell cycle arrest in cancer cells, which can be used in the research of HR-positive and HER2-negative breast cancer and hepatocellular carcinoma.

PD 0332991 (Palbociclib) HCl Chemical Structure

Size Price Stock Qty
10mM (in 1mL DMSO)
$61.00
In stock
5mg
$38.00
In stock
25mg
$67.00
In stock

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Sample solution is provided at 25 µL, 10mM.

Product Documents

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Protocol

Cell experiment [1]:

Cell lines

Human ESCC cell lines EC109 and EC9706 cells

Preparation Method

Cellular senescence was assayed by measuring senescence‐associated β‐galactosidase (SA‐β‐gal) activity. Cells were grown in 6‐well flat‐bottom plates for 24 h and then treated without or with 2.5 μM PD‐0332991 for 6 days.

Reaction Conditions

2.5 μM; for 6 days

Applications

Treatment with PD‐0332991 drastically increased the activity of SA‐β‐gal, a marker for senescent cells in EC109 and EC9706 cells.

Animal experiment [2]:

Animal models

Female 6-week-old athymic nude mice (BALB/c Slc-nu/nu)

Preparation Method

In mice bearing human endometrial cancer, daily p.o. dosing for 21 days with PD-0332991 (50 or 150 ng/kg) suppressed tumor growth.

Dosage form

50 or 150 ng/kg; p.o.

Applications

The Ki67 index in the PD-0332991-treated group was significantly lower than that in the control group. Furthermore, the phospho-Rb expression of the PD-0332991-treated group was significantly lower than that in the control group.

References:

[1]. Chen L, et al. Dual cyclin-dependent kinase 4/6 inhibition by PD-0332991 induces apoptosis and senescence in oesophageal squamous cell carcinoma cells. Br J Pharmacol. 2017 Aug;174(15):2427-2443. 

[2]. Tanaka T, et al. The efficacy of the cyclin-dependent kinase 4/6 inhibitor in endometrial cancer. PLoS One. 2017 May 4;12(5):e0177019. 

Background

PD 0332991, as an orally active potent and highly selective inhibitor of CDK4 and CDK6 kinases, can block pRb phosphorylation and subsequently inducing G1 arrest in sensitive cell lines in low nanomolar concentrations. [1][2]

In vitro, single treatment with 8 μmol/L or 16 μmol/L gefinitib inhibited PC-9 cell proliferation.[3] In vitro efficacy test it shown that PD-0332991 acted as a concentration-dependent inhibitor of cell proliferation with an IC50 of 0.65 and 0.58 μM, respectively, in HEC1A and HEC108 cells, however, PD-0332991 did not inhibit cell proliferation in ECC and TEN cells, even at concentrations of up to 1 μM.[4] PD-0332991 has G0/G1 cell-cycle arrest, induction of late apoptosis, and blockade of RB phosphorylation in RCC cell lines with IC50 values ranged from 25.0 nM to 700 nM. [5] PD 0332991 inhibited the AN, RY, G401 and NS cell lines with IC50 of 0.01 µM, 0.01 µM, 0.06 µM, and 0.6 µM, respectively. And PD 0332991 at 0 to 1.0 µM concentrations induced G1 arrest in the AN, RY, G401 and NS cell lines in a concentration-dependent manner, but had no effect on YM cells.[6]

In vivo, treatment with 150 mg/kg PD 0332991 and 100 mg/kg gefitinib inhibited tumor growth, all of the mice had a tumor volume < 30 mm3 after 14 days of treatment, and 20% (2/10) of the mice were completely cured without relapse.[3] In vivo, nu/nu BALB/c nude mice with EC109 cells s.c. were treated with 150 mg/kg orally PD‐0332991, the results shown that PD‐0332991 significantly inhibited the growth curve (tumour volume versus time curve) of EC109 tumours. And the tumour weight in the PD‐0332991‐treated mice was obviously lower than the vehicle‐treated mice.[7]

References:
[1]Fry DW, et al. Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts. Mol Cancer Ther. 2004;3:1427–1438.
[2]Saab R, et al. Pharmacologic inhibition of cyclin-dependent kinase 4/6 activity arrests proliferation in myoblasts and rhabdomyosarcoma-derived cells. Mol Cancer Ther. 2006;5:1299–1308. doi: 10.1158/1535-7163.MCT-05-0383. 
[3]Liu M, et al. PD 0332991, a selective cyclin D kinase 4/6 inhibitor, sensitizes lung cancer cells to treatment with epidermal growth factor receptor tyrosine kinase inhibitors. Oncotarget. 2016 Dec 20;7(51):84951-84964. 
[4]Tanaka T, et al. The efficacy of the cyclin-dependent kinase 4/6 inhibitor in endometrial cancer. PLoS One. 2017 May 4;12(5):e0177019. 
[5]Logan JE, et al. PD-0332991, a potent and selective inhibitor of cyclin-dependent kinase 4/6, demonstrates inhibition of proliferation in renal cell carcinoma at nanomolar concentrations and molecular markers predict for sensitivity. Anticancer Res. 2013 Aug;33(8):2997-3004.
[6]Katsumi Y, et al. Sensitivity of malignant rhabdoid tumor cell lines to PD 0332991 is inversely correlated with p16 expression. Biochem Biophys Res Commun. 2011 Sep 16;413(1):62-8. 
[7] Chen L, et al. Dual cyclin-dependent kinase 4/6 inhibition by PD-0332991 induces apoptosis and senescence in oesophageal squamous cell carcinoma cells. Br J Pharmacol. 2017 Aug;174(15):2427-2443.

Chemical Properties

Cas No. 827022-32-2 SDF
Synonyms PD0332991;PD-0332991;PD 0332991
Chemical Name 6-acetyl-8-cyclopentyl-5-methyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one hydrochloride
Canonical SMILES O=C1N(C2=NC(NC3=NC=C(C=C3)N4CCNCC4)=NC=C2C(C)=C1C(C)=O)C5CCCC5.Cl
Formula C24H30ClN7O2 M.Wt 483.99
Solubility ≥ 2.4mg/mL in DMSO, ≥ 24.2mg/mL in Water, ≥ 2.79 mg/mL in EtOH with ultrasonic and warming Storage Store at -20°C
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
Shipping Condition Evaluation sample solution : ship with blue ice
All other available size: ship with RT , or blue ice upon request

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Research Update

PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro

Breast Cancer Res2009;11(5):R77.PMID: 19874578DOI: 10.1186/bcr2419

Introduction: Alterations in cell cycle regulators have been implicated in human malignancies including breast cancer. PD 0332991 is an orally active, highly selective inhibitor of the cyclin D kinases (CDK)4 and CDK6 with ability to block retinoblastoma (Rb) phosphorylation in the low nanomolar range. To identify predictors of response, we determined the in vitro sensitivity to PD 0332991 across a panel of molecularly characterized human breast cancer cell lines.
Methods: Forty-seven human breast cancer and immortalized cell lines representing the known molecular subgroups of breast cancer were treated with PD 0332991 to determine IC50 values. These data were analyzed against baseline gene expression data to identify genes associated with PD 0332991 response.
Results: Cell lines representing luminal estrogen receptor-positive (ER+) subtype (including those that are HER2 amplified) were most sensitive to growth inhibition by PD 0332991 while nonluminal/basal subtypes were most resistant. Analysis of variance identified 450 differentially expressed genes between sensitive and resistant cells. pRb and cyclin D1 were elevated and CDKN2A (p16) was decreased in the most sensitive lines. Cell cycle analysis showed G0/G1 arrest in sensitive cell lines and Western blot analysis demonstrated that Rb phosphorylation is blocked in sensitive lines but not resistant lines. PD 0332991 was synergistic with tamoxifen and trastuzumab in ER+ and HER2-amplified cell lines, respectively. PD 0332991 enhanced sensitivity to tamoxifen in cell lines with conditioned resistance to ER blockade.
Conclusions: These studies suggest a role for CDK4/6 inhibition in some breast cancers and identify criteria for patient selection in clinical studies of PD 0332991

Palbociclib (PD-0332991) (PD-0332991), a selective CDK4/6 inhibitor, restricts tumour growth in preclinical models of hepatocellular carcinoma

Gut2017 Jul;66(7):1286-1296.PMID: 27849562DOI: 10.1136/gutjnl-2016-312268

Objective: Advanced hepatocellular carcinoma (HCC) is a lethal malignancy with limited treatment options. Palbociclib, a well-tolerated and selective CDK4/6 inhibitor, has shown promising results in the treatment of retinoblastoma (RB1)-positive breast cancer. RB1 is rarely mutated in HCC, suggesting that Palbociclib could potentially be used for HCC therapy. Here, we provide a comprehensive characterisation of the efficacy of Palbociclib in multiple preclinical models of HCC.
Design: The effects of Palbociclib on cell proliferation, cellular senescence and cell death were investigated in a panel of human liver cancer cell lines, in ex vivo human HCC samples, in a genetically engineered mouse model of liver cancer, and in human HCC xenografts in vivo. The mechanisms of intrinsic and acquired resistance to Palbociclib were assessed in human liver cancer cell lines and human HCC samples by protein and gene expression analyses.
Results: Palbociclib suppressed cell proliferation in human liver cancer cell lines by promoting a reversible cell cycle arrest. Intrinsic and acquired resistance to Palbociclib was determined by loss of RB1. A signature of 'RB1 loss of function' was found in <30% of HCC samples. Palbociclib, alone or combined with sorafenib, the standard of care for HCC, impaired tumour growth in vivo and significantly increased survival.
Conclusions: Palbociclib shows encouraging results in preclinical models of HCC and represents a novel therapeutic strategy for HCC treatment, alone or particularly in combination with sorafenib. Palbociclib could potentially benefit patients with RB1-proficient tumours, which account for 70% of all patients with HCC.

Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts

Mol Cancer Ther2004 Nov;3(11):1427-38.PMID: 15542782DOI: 10.1111/1759-7714.13866

PD 0332991 is a highly specific inhibitor of cyclin-dependent kinase 4 (Cdk4) (IC50, 0.011 micromol/L) and Cdk6 (IC50, 0.016 micromol/L), having no activity against a panel of 36 additional protein kinases. It is a potent antiproliferative agent against retinoblastoma (Rb)-positive tumor cells in vitro, inducing an exclusive G1 arrest, with a concomitant reduction of phospho-Ser780/Ser795 on the Rb protein. Oral administration of PD 0332991 to mice bearing the Colo-205 human colon carcinoma produces marked tumor regression. Therapeutic doses of PD 0332991 cause elimination of phospho-Rb and the proliferative marker Ki-67 in tumor tissue and down-regulation of genes under the transcriptional control of E2F. The results indicate that inhibition of Cdk4/6 alone is sufficient to cause tumor regression and a net reduction in tumor burden in some tumors.

PD-0332991 combined with cisplatin inhibits nonsmall cell lung cancer and reversal of cisplatin resistance

Thorac Cancer2021 Mar;12(6):924-931.PMID: 33534964DOI: 10.1111/1759-7714.13866

Background: Acquired resistance of chemotherapy, especially cisplatin, is a major challenge in lung cancer treatment. We conducted this study to examine whether a cyclin D kinase 4/6 (CDK4/6) inhibitor, PD 0332991, could reverse cisplatin resistance in human lung cancer cells. In addition, we explored the underlying mechanisms.
Method: We used CCK-8 assay to got the IC50 of PD-0332991 and cisplatin in A549 and A549/CDDP respectively. CCK-8 assay, CalcuSyn 2.0 software, cell cycle distribution and apoptosis used to identify PD-0332991 could reverse the acquired resistance of cisplatin. At last, western-blot used to show the mechanism of PD-0332991 enhances the effects of cisplatin.
Results: We found that PD-0332991 potentiated cisplatin-induced growth inhibition in both cisplatin-sensitive (A549) and cisplatin-resistant (A549/CDDP) cells via downregulation of the proliferation, induction of apoptosis (A549 increased to 7.06%; A549/CDDP increased to 7.03%), and G0/G1 cell cycle arrest (A549 increased to 9.15%; A549/CDDP increased to 49.92%). Western blot analysis revealed that PD-0332991 enhance the effect of cisplatin through inhibit Rb-E2Fs pathway.
Conclusions: These findings suggest that PD-0332991 could reverse the acquired resistance of cisplatin in lung cancer cells and provide a novel treatment strategy for lung cancer patients with cisplatin resistance.

Palbociclib (PD-0332991) pharmacokinetics in subjects with impaired renal function

Cancer Chemother Pharmacol2020 Dec;86(6):701-710.PMID: 33037918DOI: 10.1007/s00280-020-04163-4

Purpose: This publication describes an evaluation of the impact of different degrees of renal impairment on the pharmacokinetics and safety of Palbociclib after a single 125-mg oral dose.
Methods: Thirty-one subjects were assigned to different renal function groups. Serial blood sampling for pharmacokinetics was performed up to 120 h and 168 h post-Palbociclib dose for subjects with normal and impaired renal function, respectively. A separate blood sample was collected at pre-dose and 8 h after dosing to measure plasma protein binding. Plasma Palbociclib was measured using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Plasma protein binding samples were processed by equilibrium dialysis and measured by a validated LC-MS/MS method.
Results: Plasma Palbociclib exposure was higher in subjects with renal impairment than in subjects with normal renal function; however, there were no marked differences in exposure across subjects with mild, moderate, and severe renal impairment. Total plasma exposure AUCinf increased by 39%, 42%, and 31% with mild, moderate, and severe renal impairment, respectively, relative to subjects with normal renal function. Peak exposure Cmax increased by 17%, 12%, and 15% for mild, moderate, and severe impairment, respectively. There was no obvious trend in the mean fu with worsening renal function. The PBPK model adequately described Palbociclib exposure observed in subjects with moderate or severe renal impairment from this study.
Conclusion: Palbociclib was safe and well-tolerated in a small population of subjects with normal and impaired renal function after a single oral 125 mg dose. No dose adjustment is required in patients with renal impairment.

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