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)
Molecular Formula | C2H6O4S |
Molecular Weight | 126.132 |
Charge | 0 |
Count |
|
Stereochemistry | ACHIRAL |
Additional Stereochemistry | No |
Defined Stereocenters | 0 / 0 |
E/Z Centers | 0 |
Optical Activity | NONE |
Molecular Formula | C24H29N7O2 |
Molecular Weight | 447.5328 |
Charge | 0 |
Count |
|
Stereochemistry | ACHIRAL |
Additional Stereochemistry | No |
Defined Stereocenters | 0 / 0 |
E/Z Centers | 0 |
Optical Activity | NONE |
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 Date1.42292156E12 |
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 |
---|---|---|
Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts. | 2004 Nov |
|
Targeting the cell division cycle in cancer: CDK and cell cycle checkpoint kinase inhibitors. | 2005 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 |
|
Pharmacologic inhibition of cyclin-dependent kinase 4/6 activity arrests proliferation in myoblasts and rhabdomyosarcoma-derived cells. | 2006 May |
|
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 |
|
Treatment of growing teratoma syndrome. | 2009 Jan 22 |
|
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 |
|
[CDK4, a specific target in the treatment of lung adenocarcinomas mutated for KRAS]. | 2010 Dec |
|
A synthetic lethal interaction between K-Ras oncogenes and Cdk4 unveils a therapeutic strategy for non-small cell lung carcinoma. | 2010 Jul 13 |
|
Therapeutic CDK4/6 inhibition in breast cancer: key mechanisms of response and failure. | 2010 Jul 15 |
|
Pattern of retinoblastoma pathway inactivation dictates response to CDK4/6 inhibition in GBM. | 2010 Jun 22 |
|
Proliferative suppression by CDK4/6 inhibition: complex function of the retinoblastoma pathway in liver tissue and hepatoma cells. | 2010 May |
|
RB-pathway disruption in breast cancer: differential association with disease subtypes, disease-specific prognosis and therapeutic response. | 2010 Oct 15 |
|
A bioinformatical and functional approach to identify novel strategies for chemoprevention of colorectal cancer. | 2011 Apr 28 |
|
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 |
|
[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 |
|
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 |
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).
Substance Class |
Chemical
Created
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