U.S. Department of Health & Human Services Divider Arrow National Institutes of Health Divider Arrow NCATS

Details

Stereochemistry ACHIRAL
Molecular Formula C24H29N7O2.C2H6O4S
Molecular Weight 573.6665
Optical Activity NONE
Defined Stereocenters 0 / 0
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of PALBOCICLIB ISETHIONATE

SMILES

Cc1c2cnc(Nc3ccc(cn3)N4CCNCC4)nc2n(C5CCCC5)c(=O)c1C(=O)C.C(CS(=O)(=O)O)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)

HIDE SMILES / InChI

Molecular Formula C2H6O4S
Molecular Weight 126.1328
Charge 0
Count
Stereochemistry ACHIRAL
Additional Stereochemistry No
Defined Stereocenters 0 / 0
E/Z Centers 0
Optical Activity NONE

Molecular Formula C24H29N7O2
Molecular Weight 447.5337
Charge 0
Count
Stereochemistry ACHIRAL
Additional Stereochemistry No
Defined Stereocenters 0 / 0
E/Z Centers 0
Optical Activity NONE

Description
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

Curator's Comment:: # Onyx Pharmaceuticals; Pfizer

Approval Year

TargetsConditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
IBRANCE

Approved Use

IBRANCE 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 Date

1.42292156E12
Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
104.1 ng/mL
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

AUC

ValueDoseCo-administeredAnalytePopulation
2483 ng × h/mL
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

T1/2

ValueDoseCo-administeredAnalytePopulation
23.9 h
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

Doses

DosePopulationAdverse 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%)
Asthenia (1%)
Fatigue (1%)
Sources:
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)
Vomiting (1 patient)
Dizziness (1 patient)
Sources: Page: p. 112
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

AEs

AESignificanceDosePopulation
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
OverviewDrug as perpetrator​

Drug as perpetrator​

TargetModalityActivityMetaboliteClinical evidence
no [IC50 >30 uM]
no [IC50 >30 uM]
no [IC50 >30 uM]
no [IC50 >30 uM]
no [IC50 >30 uM]
no [IC50 >30 uM]
no [IC50 >30 uM]
no
no
no
no
no
no
no
no
no
no
no
no
no
no
no
no
no
weak
Drug as victimTox targets

Tox targets

TargetModalityActivityMetaboliteClinical evidence
PubMed

PubMed

TitleDatePubMed
Primary care pediatrics vs. family practice: a nonissue.
1983 Aug
Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts.
2004 Nov
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
CDK inhibitors as potential breast cancer therapeutics: new evidence for enhanced efficacy in ER+ disease.
2009
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
Stem cell factor and interleukin-2/15 combine to enhance MAPK-mediated proliferation of human natural killer cells.
2009 Mar 19
The landscape of somatic copy-number alteration across human cancers.
2010 Feb 18
Proliferative suppression by CDK4/6 inhibition: complex function of the retinoblastoma pathway in liver tissue and hepatoma cells.
2010 May
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
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
Selective CDK4/6 inhibition with tumor responses by PD0332991 in patients with mantle cell lymphoma.
2012 May 17
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
Synergism of cyclin-dependent kinase inhibitors with camptothecin derivatives in small cell lung cancer cell lines.
2014 Feb 17
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
Phase 2 trial of the cyclin-dependent kinase 4/6 inhibitor palbociclib in patients with retinoblastoma protein-expressing germ cell tumors.
2015 May 1
Patents

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
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
by admin
on Sat Jun 26 08:28:40 UTC 2021
Edited
by admin
on Sat Jun 26 08:28:40 UTC 2021
Record UNII
W1NYL2IRDR
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
PALBOCICLIB ISETHIONATE
USAN   WHO-DD  
USAN  
Official Name English
PD-0332991-0054
Code English
PD-03329910054
Code English
PALBOCICLIB ISETHIONATE [USAN]
Common Name English
PD 0332991-0054
Code English
PF-0008066573
Code English
ETHANESULFONIC ACID, 2-HYDROXY-, COMPD. WITH 6-ACETYL-8-CYCLOPENTYL-5-METHYL-2-((5-(1-PIPERAZINYL)-2-PYRIDINYL)AMINO)PYRIDO(2,3-D)PYRIMIDIN-7(8H)-ONE (1:1)
Common Name English
6-ACETYL-8-CYCLOPENTYL-5-METHYL-2-((5-(PIPERAZIN-1-YL)PYRIDIN-2-YL)AMINO(PYRIDO(2,3-D)PYRIMIDIN-7(8H)-ONE MONO(2-HYDROXYETHANESULFONATE)
Common Name English
PALBOCICLIB ISETHIONATE [WHO-DD]
Common Name English
PF-00080665-73
Code English
PALBOCICLIB ISETHIOLATE [MI]
Common Name English
Classification Tree Code System Code
NCI_THESAURUS C2185
Created by admin on Sat Jun 26 08:28:40 UTC 2021 , Edited by admin on Sat Jun 26 08:28:40 UTC 2021
NCI_THESAURUS C129825
Created by admin on Sat Jun 26 08:28:40 UTC 2021 , Edited by admin on Sat Jun 26 08:28:40 UTC 2021
Code System Code Type Description
NCI_THESAURUS
C120259
Created by admin on Sat Jun 26 08:28:40 UTC 2021 , Edited by admin on Sat Jun 26 08:28:40 UTC 2021
PRIMARY
CAS
827022-33-3
Created by admin on Sat Jun 26 08:28:40 UTC 2021 , Edited by admin on Sat Jun 26 08:28:40 UTC 2021
PRIMARY
FDA UNII
W1NYL2IRDR
Created by admin on Sat Jun 26 08:28:40 UTC 2021 , Edited by admin on Sat Jun 26 08:28:40 UTC 2021
PRIMARY
PUBCHEM
11478676
Created by admin on Sat Jun 26 08:28:40 UTC 2021 , Edited by admin on Sat Jun 26 08:28:40 UTC 2021
PRIMARY
ChEMBL
CHEMBL189963
Created by admin on Sat Jun 26 08:28:40 UTC 2021 , Edited by admin on Sat Jun 26 08:28:40 UTC 2021
PRIMARY
EPA CompTox
827022-33-3
Created by admin on Sat Jun 26 08:28:40 UTC 2021 , Edited by admin on Sat Jun 26 08:28:40 UTC 2021
PRIMARY
MERCK INDEX
M11849
Created by admin on Sat Jun 26 08:28:40 UTC 2021 , Edited by admin on Sat Jun 26 08:28:40 UTC 2021
PRIMARY
DRUG BANK
DBSALT001110
Created by admin on Sat Jun 26 08:28:40 UTC 2021 , Edited by admin on Sat Jun 26 08:28:40 UTC 2021
PRIMARY
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ACTIVE MOIETY