Details
Stereochemistry | ACHIRAL |
Molecular Formula | C24H29N7O2.C2H6O4S |
Molecular Weight | 573.664 |
Optical Activity | NONE |
Defined Stereocenters | 0 / 0 |
E/Z Centers | 0 |
Charge | 0 |
SHOW SMILES / InChI
SMILES
OCCS(O)(=O)=O.CC(=O)C1=C(C)C2=CN=C(NC3=CC=C(C=N3)N4CCNCC4)N=C2N(C5CCCC5)C1=O
InChI
InChIKey=LYYVFHRFIJKPOV-UHFFFAOYSA-N
InChI=1S/C24H29N7O2.C2H6O4S/c1-15-19-14-27-24(28-20-8-7-18(13-26-20)30-11-9-25-10-12-30)29-22(19)31(17-5-3-4-6-17)23(33)21(15)16(2)32;3-1-2-7(4,5)6/h7-8,13-14,17,25H,3-6,9-12H2,1-2H3,(H,26,27,28,29);3H,1-2H2,(H,4,5,6)
DescriptionCurator's Comment: Description was created based on several sources, including https://www.drugbank.ca/drugs/DB09073
Curator's Comment: Description was created based on several sources, including https://www.drugbank.ca/drugs/DB09073
Palbociclib is an oral, reversible, selective, small-molecule inhibitor of CDK4 and CDK6 indicated in combination with letrozole for the treatment of postmenopausal women with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer as initial endocrine-based therapy for their metastatic disease. CDK4 and CDK6 along with their regulatory partner cyclin D1 play a key role in regulating the G1- to S-phase cell-cycle transition via regulation of phosphorylation of the retinoblastoma (Rb) protein. Inhibition of these proteins leads to reduced phosphorylation of Rb, inhibition of downstream signalling, and increased tumor growth arrest. Palbociclib received an accelerated approval from the Food and Drug Administration on February 3, 2015. Palbociclib is marketed under the trade name Ibrance. IBRANCE is a kinase inhibitor indicated in combination with letrozole for the
treatment of postmenopausal women with estrogen receptor (ER)-positive,
human epidermal growth factor receptor 2 (HER2)-negative advanced breast
cancer as initial endocrine-based therapy for their metastatic disease.
Originator
Sources: http://adisinsight.springer.com/drugs/800020668
Curator's Comment: # Onyx Pharmaceuticals; Pfizer
Approval Year
Targets
Primary Target | Pharmacology | Condition | Potency |
---|---|---|---|
11.0 nM [IC50] | |||
Target ID: CHEMBL1075497 Sources: https://www.ncbi.nlm.nih.gov/pubmed/19874578 |
4.0 nM [IC50] | ||
Target ID: CHEMBL1075613 Sources: https://www.ncbi.nlm.nih.gov/pubmed/19874578 |
5.0 nM [IC50] | ||
15.0 nM [IC50] | |||
9.0 nM [IC50] |
Conditions
Condition | Modality | Targets | Highest Phase | Product |
---|---|---|---|---|
Primary | IBRANCE Approved UseIBRANCE is indicated in combination with letrozole for the treatment of postmenopausal women with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer as initial endocrine-based therapy for their metastatic disease. This indication is approved under accelerated approval based on progression-free survival (PFS) Launch Date2015 |
Cmax
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
104.1 ng/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/26991823 |
125 mg single, oral dose: 125 mg route of administration: Oral experiment type: SINGLE co-administered: |
PALBOCICLIB plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED |
AUC
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
2483 ng × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/26991823 |
125 mg single, oral dose: 125 mg route of administration: Oral experiment type: SINGLE co-administered: |
PALBOCICLIB plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED |
T1/2
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
23.9 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/26991823 |
125 mg single, oral dose: 125 mg route of administration: Oral experiment type: SINGLE co-administered: |
PALBOCICLIB plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED |
Doses
Dose | Population | Adverse events |
---|---|---|
150 mg 1 times / day multiple, oral Highest studied dose Dose: 150 mg, 1 times / day Route: oral Route: multiple Dose: 150 mg, 1 times / day Sources: |
unhealthy, 54 years (range: 22–77 years) n = 3 Health Status: unhealthy Age Group: 54 years (range: 22–77 years) Sex: M+F Population Size: 3 Sources: |
|
125 mg 1 times / day steady, oral MTD|RP2D Dose: 125 mg, 1 times / day Route: oral Route: steady Dose: 125 mg, 1 times / day Sources: |
unhealthy, 54 years (range: 22–77 years) n = 22 Health Status: unhealthy Age Group: 54 years (range: 22–77 years) Sex: M+F Population Size: 22 Sources: |
DLT: Neutropenia... Dose limiting toxicities: Neutropenia (grade 3, 1 patient) Sources: |
150 mg 1 times / day steady, oral Dose: 150 mg, 1 times / day Route: oral Route: steady Dose: 150 mg, 1 times / day Sources: |
unhealthy, 54 years (range: 22–77 years) n = 3 Health Status: unhealthy Age Group: 54 years (range: 22–77 years) Sex: M+F Population Size: 3 Sources: |
DLT: Neutropenia... Dose limiting toxicities: Neutropenia (grade 3-4, 2 patients) Sources: |
75 mg 1 times / day steady, oral Dose: 75 mg, 1 times / day Route: oral Route: steady Dose: 75 mg, 1 times / day Sources: |
unhealthy, 54 years (range: 22–77 years) n = 7 Health Status: unhealthy Age Group: 54 years (range: 22–77 years) Sex: M+F Population Size: 7 Sources: |
DLT: Neutropenia... Dose limiting toxicities: Neutropenia (grade 3-4, 2 patients) Sources: |
125 mg 1 times / day steady, oral Recommended Dose: 125 mg, 1 times / day Route: oral Route: steady Dose: 125 mg, 1 times / day Co-administed with:: letrozole(2.5 mg/day) Sources: |
unhealthy, 63 years (range: 38 - 89 years) n = 83 Health Status: unhealthy Age Group: 63 years (range: 38 - 89 years) Sex: M+F Population Size: 83 Sources: |
Disc. AE: Neutropenia, Asthenia... AEs leading to discontinuation/dose reduction: Neutropenia (6%) Sources: Asthenia (1%) Fatigue (1%) |
200 mg 1 times / day multiple, oral Overdose Dose: 200 mg, 1 times / day Route: oral Route: multiple Dose: 200 mg, 1 times / day Sources: Page: p. 112 |
unhealthy, adult n = 1 Health Status: unhealthy Age Group: adult Population Size: 1 Sources: Page: p. 112 |
Other AEs: Nausea, Vomiting... Other AEs: Nausea (1 patient) Sources: Page: p. 112Vomiting (1 patient) Dizziness (1 patient) |
250 mg 1 times / day multiple, oral Overdose Dose: 250 mg, 1 times / day Route: oral Route: multiple Dose: 250 mg, 1 times / day Sources: Page: p. 112 |
unhealthy, adult n = 1 Health Status: unhealthy Age Group: adult Population Size: 1 Sources: Page: p. 112 |
Disc. AE: Neutropenia... AEs leading to discontinuation/dose reduction: Neutropenia (grade 4, 1 patient) Sources: Page: p. 112 |
AEs
AE | Significance | Dose | Population |
---|---|---|---|
Neutropenia | grade 3, 1 patient DLT |
125 mg 1 times / day steady, oral MTD|RP2D Dose: 125 mg, 1 times / day Route: oral Route: steady Dose: 125 mg, 1 times / day Sources: |
unhealthy, 54 years (range: 22–77 years) n = 22 Health Status: unhealthy Age Group: 54 years (range: 22–77 years) Sex: M+F Population Size: 22 Sources: |
Neutropenia | grade 3-4, 2 patients DLT |
150 mg 1 times / day steady, oral Dose: 150 mg, 1 times / day Route: oral Route: steady Dose: 150 mg, 1 times / day Sources: |
unhealthy, 54 years (range: 22–77 years) n = 3 Health Status: unhealthy Age Group: 54 years (range: 22–77 years) Sex: M+F Population Size: 3 Sources: |
Neutropenia | grade 3-4, 2 patients DLT |
75 mg 1 times / day steady, oral Dose: 75 mg, 1 times / day Route: oral Route: steady Dose: 75 mg, 1 times / day Sources: |
unhealthy, 54 years (range: 22–77 years) n = 7 Health Status: unhealthy Age Group: 54 years (range: 22–77 years) Sex: M+F Population Size: 7 Sources: |
Asthenia | 1% Disc. AE |
125 mg 1 times / day steady, oral Recommended Dose: 125 mg, 1 times / day Route: oral Route: steady Dose: 125 mg, 1 times / day Co-administed with:: letrozole(2.5 mg/day) Sources: |
unhealthy, 63 years (range: 38 - 89 years) n = 83 Health Status: unhealthy Age Group: 63 years (range: 38 - 89 years) Sex: M+F Population Size: 83 Sources: |
Fatigue | 1% Disc. AE |
125 mg 1 times / day steady, oral Recommended Dose: 125 mg, 1 times / day Route: oral Route: steady Dose: 125 mg, 1 times / day Co-administed with:: letrozole(2.5 mg/day) Sources: |
unhealthy, 63 years (range: 38 - 89 years) n = 83 Health Status: unhealthy Age Group: 63 years (range: 38 - 89 years) Sex: M+F Population Size: 83 Sources: |
Neutropenia | 6% Disc. AE |
125 mg 1 times / day steady, oral Recommended Dose: 125 mg, 1 times / day Route: oral Route: steady Dose: 125 mg, 1 times / day Co-administed with:: letrozole(2.5 mg/day) Sources: |
unhealthy, 63 years (range: 38 - 89 years) n = 83 Health Status: unhealthy Age Group: 63 years (range: 38 - 89 years) Sex: M+F Population Size: 83 Sources: |
Dizziness | 1 patient | 200 mg 1 times / day multiple, oral Overdose Dose: 200 mg, 1 times / day Route: oral Route: multiple Dose: 200 mg, 1 times / day Sources: Page: p. 112 |
unhealthy, adult n = 1 Health Status: unhealthy Age Group: adult Population Size: 1 Sources: Page: p. 112 |
Nausea | 1 patient | 200 mg 1 times / day multiple, oral Overdose Dose: 200 mg, 1 times / day Route: oral Route: multiple Dose: 200 mg, 1 times / day Sources: Page: p. 112 |
unhealthy, adult n = 1 Health Status: unhealthy Age Group: adult Population Size: 1 Sources: Page: p. 112 |
Vomiting | 1 patient | 200 mg 1 times / day multiple, oral Overdose Dose: 200 mg, 1 times / day Route: oral Route: multiple Dose: 200 mg, 1 times / day Sources: Page: p. 112 |
unhealthy, adult n = 1 Health Status: unhealthy Age Group: adult Population Size: 1 Sources: Page: p. 112 |
Neutropenia | grade 4, 1 patient Disc. AE |
250 mg 1 times / day multiple, oral Overdose Dose: 250 mg, 1 times / day Route: oral Route: multiple Dose: 250 mg, 1 times / day Sources: Page: p. 112 |
unhealthy, adult n = 1 Health Status: unhealthy Age Group: adult Population Size: 1 Sources: Page: p. 112 |
Overview
CYP3A4 | CYP2C9 | CYP2D6 | hERG |
---|---|---|---|
OverviewOther
Other Inhibitor | Other Substrate | Other Inducer |
---|---|---|
Drug as perpetrator
Drug as victim
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
yes | ||||
yes | ||||
yes | ||||
yes |
Tox targets
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/207103Orig1s000PharmR.pdf#page=71 Page: 71.0 |
PubMed
Title | Date | PubMed |
---|---|---|
Primary care pediatrics vs. family practice: a nonissue. | 1983 Aug |
|
A novel orally active small molecule potently induces G1 arrest in primary myeloma cells and prevents tumor growth by specific inhibition of cyclin-dependent kinase 4/6. | 2006 Aug 1 |
|
Toward understanding the structural basis of cyclin-dependent kinase 6 specific inhibition. | 2006 Jun 29 |
|
Expression of p16Ink4a compensates for p18Ink4c loss in cyclin-dependent kinase 4/6-dependent tumors and tissues. | 2007 May 15 |
|
Pharmacologic inhibition of CDK4/6: mechanistic evidence for selective activity or acquired resistance in acute myeloid leukemia. | 2007 Sep 15 |
|
A novel therapeutic combination using PD 0332991 and bortezomib: study in the 5T33MM myeloma model. | 2008 Jul 15 |
|
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. | 2009 |
|
Advancing bioluminescence imaging technology for the evaluation of anticancer agents in the MDA-MB-435-HAL-Luc mammary fat pad and subrenal capsule tumor models. | 2009 Jan 1 |
|
Treatment of growing teratoma syndrome. | 2009 Jan 22 |
|
Stem cell factor and interleukin-2/15 combine to enhance MAPK-mediated proliferation of human natural killer cells. | 2009 Mar 19 |
|
Epigenetic silencing of the tumor suppressor microRNA Hsa-miR-124a regulates CDK6 expression and confers a poor prognosis in acute lymphoblastic leukemia. | 2009 May 15 |
|
Therapeutic CDK4/6 inhibition in breast cancer: key mechanisms of response and failure. | 2010 Jul 15 |
|
RB-pathway disruption in breast cancer: differential association with disease subtypes, disease-specific prognosis and therapeutic response. | 2010 Oct 15 |
|
Early G₁ cyclin-dependent kinases as prognostic markers and potential therapeutic targets in esophageal adenocarcinoma. | 2011 Jul 1 |
|
Therapeutically activating RB: reestablishing cell cycle control in endocrine therapy-resistant breast cancer. | 2011 Jun |
|
Expression of p16 and retinoblastoma determines response to CDK4/6 inhibition in ovarian cancer. | 2011 Mar 15 |
|
A systematic screen for CDK4/6 substrates links FOXM1 phosphorylation to senescence suppression in cancer cells. | 2011 Nov 15 |
|
Phase I, dose-escalation trial of the oral cyclin-dependent kinase 4/6 inhibitor PD 0332991, administered using a 21-day schedule in patients with advanced cancer. | 2012 Jan 15 |
|
Therapeutic response to CDK4/6 inhibition in breast cancer defined by ex vivo analyses of human tumors. | 2012 Jul 15 |
|
The CDK4/6 inhibitor PD0332991 reverses epithelial dysplasia associated with abnormal activation of the cyclin-CDK-Rb pathway. | 2012 Jun |
|
Cdk4/6 inhibition induces epithelial-mesenchymal transition and enhances invasiveness in pancreatic cancer cells. | 2012 Oct |
|
Therapeutic targeting of the cyclin D3:CDK4/6 complex in T cell leukemia. | 2012 Oct 16 |
|
The requirement for cyclin D function in tumor maintenance. | 2012 Oct 16 |
|
Attenuation of the retinoblastoma pathway in pancreatic neuroendocrine tumors due to increased cdk4/cdk6. | 2012 Sep 1 |
|
PD-0332991, a CDK4/6 inhibitor, significantly prolongs survival in a genetically engineered mouse model of brainstem glioma. | 2013 |
|
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. | 2013 Aug |
|
Inhibition of cyclin-dependent kinase 6 suppresses cell proliferation and enhances radiation sensitivity in medulloblastoma cells. | 2013 Jan |
|
A CDK4/6 inhibitor enhances cytotoxicity of paclitaxel in lung adenocarcinoma cells harboring mutant KRAS as well as wild-type KRAS. | 2013 Jul |
|
Phase II trial of the CDK4 inhibitor PD0332991 in patients with advanced CDK4-amplified well-differentiated or dedifferentiated liposarcoma. | 2013 Jun 1 |
|
Induction of prolonged early G1 arrest by CDK4/CDK6 inhibition reprograms lymphoma cells for durable PI3Kδ inhibition through PIK3IP1. | 2013 Jun 15 |
|
Targeting cell cycle and hormone receptor pathways in cancer. | 2013 Nov 28 |
|
MLL fusion-driven activation of CDK6 potentiates proliferation in MLL-rearranged infant ALL. | 2014 |
|
[Effect of PD0332991 on biological activity of hematopoietic stem cells in mice]. | 2014 Feb |
|
Synergism of cyclin-dependent kinase inhibitors with camptothecin derivatives in small cell lung cancer cell lines. | 2014 Feb 17 |
|
CDK4/6 inhibition provides a potent adjunct to Her2-targeted therapies in preclinical breast cancer models. | 2014 Jul |
|
Loss of CDKN2A expression is a frequent event in primary invasive melanoma and correlates with sensitivity to the CDK4/6 inhibitor PD0332991 in melanoma cell lines. | 2014 Jul |
|
CDK4/6 and IGF1 receptor inhibitors synergize to suppress the growth of p16INK4A-deficient pancreatic cancers. | 2014 Jul 15 |
|
Palbociclib: first global approval. | 2015 Apr |
|
The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. | 2015 Jan |
|
Palbociclib Extends Survival in Advanced Breast Cancer. | 2015 Jul |
|
Palbociclib in Hormone-Receptor-Positive Advanced Breast Cancer. | 2015 Jul 16 |
|
CDK 4/6 inhibitor palbociclib (PD0332991) in Rb+ advanced breast cancer: phase II activity, safety, and predictive biomarker assessment. | 2015 Mar 1 |
Sample Use Guides
IBRANCE capsules (Palbociclib) are taken orally with food in combination with letrozole. Recommended starting dose: 125 mg once daily taken with food for 21 days followed by 7 days off treatment
Route of Administration:
Oral
In Vitro Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/19874578
Palbociclib (100 nM) significantly
blocks phoshorylation of pRb (phospho-Rb) at serine 780 in sensitive human breast cancer cell lines (IC50 < 150 nM).
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NCI_THESAURUS |
C2185
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C129825
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C120259
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827022-33-3
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W1NYL2IRDR
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11478676
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CHEMBL189963
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m11849
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DBSALT001110
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ACTIVE MOIETY
PARENT (SALT/SOLVATE)
SUBSTANCE RECORD