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Details

Stereochemistry ACHIRAL
Molecular Formula C24H29N7O2
Molecular Weight 447.5328
Optical Activity UNSPECIFIED
Defined Stereocenters 0 / 0
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of PALBOCICLIB

SMILES

CC(=O)C1=C(C)C2=C(N=C(NC3=CC=C(C=N3)N4CCNCC4)N=C2)N(C5CCCC5)C1=O

InChI

InChIKey=AHJRHEGDXFFMBM-UHFFFAOYSA-N
InChI=1S/C24H29N7O2/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/h7-8,13-14,17,25H,3-6,9-12H2,1-2H3,(H,26,27,28,29)

HIDE SMILES / InChI

Molecular Formula C24H29N7O2
Molecular Weight 447.5328
Charge 0
Count
Stereochemistry ACHIRAL
Additional Stereochemistry
Defined Stereocenters 0 / 0
E/Z Centers 0
Optical Activity NONE

Description

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

Approval Year

PubMed

PubMed

TitleDatePubMed
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
Pharmacologic inhibition of cyclin-dependent kinase 4/6 activity arrests proliferation in myoblasts and rhabdomyosarcoma-derived cells.
2006 May
Mantle cell lymphoma cells express predominantly cyclin D1a isoform and are highly sensitive to selective inhibition of CDK4 kinase activity.
2006 Sep 1
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
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
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
The landscape of somatic copy-number alteration across human cancers.
2010 Feb 18
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
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
A systematic screen for CDK4/6 substrates links FOXM1 phosphorylation to senescence suppression in cancer cells.
2011 Nov 15
p16-Cdk4-Rb axis controls sensitivity to a cyclin-dependent kinase inhibitor PD0332991 in glioblastoma xenograft cells.
2012 Jul
[(18)F]FLT-PET imaging does not always "light up" proliferating tumor cells.
2012 Mar 1
Cdk4/6 inhibition induces epithelial-mesenchymal transition and enhances invasiveness in pancreatic cancer cells.
2012 Oct
The requirement for cyclin D function in tumor maintenance.
2012 Oct 16
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
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
MLL fusion-driven activation of CDK6 potentiates proliferation in MLL-rearranged infant ALL.
2014
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
Palbociclib Extends Survival in Advanced Breast Cancer.
2015 Jul
Patents

Sample Use Guides

In Vivo Use Guide
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
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 Mon Oct 21 20:39:58 UTC 2019
Edited
by admin
on Mon Oct 21 20:39:58 UTC 2019
Record UNII
G9ZF61LE7G
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
PALBOCICLIB
DASH   INN   USAN   WHO-DD  
INN   USAN  
Official Name English
6-ACETYL-8-CYCLOPENTYL-5-METHYL-2-((5-(PIPERAZIN-1-YL)PYRIDIN-2-YL)AMINO)-8H-PYRIDO(2,3-D)PYRIMIDIN-7-ONE
Systematic Name English
IBRANCE
Brand Name English
PYRIDO(2,3-D)PYRIMIDIN-7(8H)-ONE, 6-ACETYL-8-CYCLOPENTYL-5-METHYL-2-((5-(1-PIPERAZINYL)-2-PYRIDINYL)AMINO)-
Systematic 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
Common Name English
PALBOCICLIB [USAN]
Common Name English
PALBOCICLIB [JAN]
Common Name English
PD-0332991
Code English
PALBOCICLIB [INN]
Common Name English
PALBOCICLIB [WHO-DD]
Common Name English
Classification Tree Code System Code
WHO-ATC L01XE33
Created by admin on Mon Oct 21 20:39:58 UTC 2019 , Edited by admin on Mon Oct 21 20:39:58 UTC 2019
NCI_THESAURUS C2185
Created by admin on Mon Oct 21 20:39:58 UTC 2019 , Edited by admin on Mon Oct 21 20:39:58 UTC 2019
NCI_THESAURUS C129825
Created by admin on Mon Oct 21 20:39:58 UTC 2019 , Edited by admin on Mon Oct 21 20:39:58 UTC 2019
NDF-RT N0000175605
Created by admin on Mon Oct 21 20:39:58 UTC 2019 , Edited by admin on Mon Oct 21 20:39:58 UTC 2019
Code System Code Type Description
EVMPD
SUB177204
Created by admin on Mon Oct 21 20:39:58 UTC 2019 , Edited by admin on Mon Oct 21 20:39:58 UTC 2019
PRIMARY
NDF-RT
N0000175082
Created by admin on Mon Oct 21 20:39:58 UTC 2019 , Edited by admin on Mon Oct 21 20:39:58 UTC 2019
PRIMARY Kinase Inhibitors [MoA]
NCI_THESAURUS
C49176
Created by admin on Mon Oct 21 20:39:58 UTC 2019 , Edited by admin on Mon Oct 21 20:39:58 UTC 2019
PRIMARY
ChEMBL
CHEMBL189963
Created by admin on Mon Oct 21 20:39:58 UTC 2019 , Edited by admin on Mon Oct 21 20:39:58 UTC 2019
PRIMARY
NDF-RT
N0000190114
Created by admin on Mon Oct 21 20:39:58 UTC 2019 , Edited by admin on Mon Oct 21 20:39:58 UTC 2019
PRIMARY Cytochrome P450 3A Inhibitors [MoA]
RXCUI
1601374
Created by admin on Mon Oct 21 20:39:58 UTC 2019 , Edited by admin on Mon Oct 21 20:39:58 UTC 2019
PRIMARY RxNorm
PUBCHEM
5330286
Created by admin on Mon Oct 21 20:39:58 UTC 2019 , Edited by admin on Mon Oct 21 20:39:58 UTC 2019
PRIMARY
INN
9802
Created by admin on Mon Oct 21 20:39:58 UTC 2019 , Edited by admin on Mon Oct 21 20:39:58 UTC 2019
PRIMARY
WIKIPEDIA
Palbociclib
Created by admin on Mon Oct 21 20:39:58 UTC 2019 , Edited by admin on Mon Oct 21 20:39:58 UTC 2019
PRIMARY
CAS
571190-30-2
Created by admin on Mon Oct 21 20:39:58 UTC 2019 , Edited by admin on Mon Oct 21 20:39:58 UTC 2019
PRIMARY
LactMed
571190-30-2
Created by admin on Mon Oct 21 20:39:58 UTC 2019 , Edited by admin on Mon Oct 21 20:39:58 UTC 2019
PRIMARY
DRUG BANK
DB09073
Created by admin on Mon Oct 21 20:39:58 UTC 2019 , Edited by admin on Mon Oct 21 20:39:58 UTC 2019
PRIMARY
IUPHAR
7380
Created by admin on Mon Oct 21 20:39:58 UTC 2019 , Edited by admin on Mon Oct 21 20:39:58 UTC 2019
PRIMARY
Related Record Type Details
SALT/SOLVATE -> PARENT
SALT/SOLVATE -> PARENT
TRANSPORTER -> SUBSTRATE
TRANSPORTER -> SUBSTRATE
EXCRETED UNCHANGED
URINE
BINDER->LIGAND
BINDING
METABOLIC ENZYME -> NON-INDUCER
METABOLIC ENZYME -> SUBSTRATE
TARGET -> INHIBITOR
IC50
EXCRETED UNCHANGED
FECAL
TARGET -> INHIBITOR
IC50
Related Record Type Details
METABOLITE -> PARENT
MAJOR
PLASMA
Related Record Type Details
ACTIVE MOIETY
Name Property Type Amount Referenced Substance Defining Parameters References
log P CHEMICAL
Biological Half-life PHARMACOKINETIC
pKa CHEMICAL
pKa CHEMICAL
Tmax PHARMACOKINETIC ORAL ADMINISTRATION

CSF/PLASMA RATIO PHARMACOKINETIC ROUTE OF ADMINISTRATION
PHARMACOKINETIC
DOSE
PHARMACOKINETIC
brain-to-plasma AUC ratios
PHARMACOKINETIC
Volume of Distribution PHARMACOKINETIC