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

cancer as initial endocrine-based therapy for their metastatic disease.

Originator

Curator's Comment:: # Onyx Pharmaceuticals; Pfizer

Approval Year

Targets

Targets

Primary TargetPharmacologyConditionPotency
11 nM [IC50]
4 nM [IC50]
5 nM [IC50]
15 nM [IC50]
9 nM [IC50]
Conditions

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

1422921600000
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)
Health Status: unhealthy
Age Group: 54 years (range: 22–77 years)
Sex: M+F
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)
Health Status: unhealthy
Age Group: 54 years (range: 22–77 years)
Sex: M+F
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)
Health Status: unhealthy
Age Group: 54 years (range: 22–77 years)
Sex: M+F
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)
Health Status: unhealthy
Age Group: 54 years (range: 22–77 years)
Sex: M+F
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
Sources:
unhealthy, 63 years (range: 38 - 89 years)
Health Status: unhealthy
Age Group: 63 years (range: 38 - 89 years)
Sex: M+F
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:
unhealthy, adult
Other AEs: Nausea, Vomiting...
Other AEs:
Nausea (1 patient)
Vomiting (1 patient)
Dizziness (1 patient)
Sources:
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:
unhealthy, adult
Disc. AE: Neutropenia...
AEs leading to
discontinuation/dose reduction:
Neutropenia (grade 4, 1 patient)
Sources:
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)
Health Status: unhealthy
Age Group: 54 years (range: 22–77 years)
Sex: M+F
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)
Health Status: unhealthy
Age Group: 54 years (range: 22–77 years)
Sex: M+F
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)
Health Status: unhealthy
Age Group: 54 years (range: 22–77 years)
Sex: M+F
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
Sources:
unhealthy, 63 years (range: 38 - 89 years)
Health Status: unhealthy
Age Group: 63 years (range: 38 - 89 years)
Sex: M+F
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
Sources:
unhealthy, 63 years (range: 38 - 89 years)
Health Status: unhealthy
Age Group: 63 years (range: 38 - 89 years)
Sex: M+F
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
Sources:
unhealthy, 63 years (range: 38 - 89 years)
Health Status: unhealthy
Age Group: 63 years (range: 38 - 89 years)
Sex: M+F
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:
unhealthy, adult
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:
unhealthy, adult
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:
unhealthy, adult
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:
unhealthy, adult
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

PubMed

PubMed

TitleDatePubMed
Primary care pediatrics vs. family practice: a nonissue.
1983 Aug
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
Pharmacologic inhibition of cyclin-dependent kinases 4 and 6 arrests the growth of glioblastoma multiforme intracranial xenografts.
2010 Apr 15
[CDK4, a specific target in the treatment of lung adenocarcinomas mutated for KRAS].
2010 Dec
The landscape of somatic copy-number alteration across human cancers.
2010 Feb 18
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
Quantitative analysis of PD 0332991 in xenograft mouse tumor tissue by a 96-well supported liquid extraction format and liquid chromatography/mass spectrometry.
2010 Nov 2
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
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
Phase I study of PD 0332991, a cyclin-dependent kinase inhibitor, administered in 3-week cycles (Schedule 2/1).
2011 Jun 7
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
Retinoblastoma protein modulates the inverse relationship between cellular proliferation and elastogenesis.
2011 Oct 21
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
p16-Cdk4-Rb axis controls sensitivity to a cyclin-dependent kinase inhibitor PD0332991 in glioblastoma xenograft cells.
2012 Jul
Therapeutic response to CDK4/6 inhibition in breast cancer defined by ex vivo analyses of human tumors.
2012 Jul 15
CDK4/6 inhibition antagonizes the cytotoxic response to anthracycline therapy.
2012 Jul 15
The CDK4/6 inhibitor PD0332991 reverses epithelial dysplasia associated with abnormal activation of the cyclin-CDK-Rb pathway.
2012 Jun
[(18)F]FLT-PET imaging does not always "light up" proliferating tumor cells.
2012 Mar 1
Multiple roles of cyclin-dependent kinase 4/6 inhibitors in cancer therapy.
2012 Mar 21
Selective CDK4/6 inhibition with tumor responses by PD0332991 in patients with mantle cell lymphoma.
2012 May 17
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
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
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