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Details

Stereochemistry ACHIRAL
Molecular Formula C23H30N8O
Molecular Weight 434.5373
Optical Activity UNSPECIFIED
Defined Stereocenters 0 / 0
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of RIBOCICLIB

SMILES

CN(C)C(=O)C1=CC2=C(N=C(NC3=CC=C(C=N3)N4CCNCC4)N=C2)N1C5CCCC5

InChI

InChIKey=RHXHGRAEPCAFML-UHFFFAOYSA-N
InChI=1S/C23H30N8O/c1-29(2)22(32)19-13-16-14-26-23(28-21(16)31(19)17-5-3-4-6-17)27-20-8-7-18(15-25-20)30-11-9-24-10-12-30/h7-8,13-15,17,24H,3-6,9-12H2,1-2H3,(H,25,26,27,28)

HIDE SMILES / InChI

Molecular Formula C23H30N8O
Molecular Weight 434.5373
Charge 0
Count
Stereochemistry ACHIRAL
Additional Stereochemistry
Defined Stereocenters 0 / 0
E/Z Centers 0
Optical Activity NONE

Description

Ribociclib, also known as LEE011, is an orally available cyclin-dependent kinase (CDK) inhibitor targeting cyclin D1/CDK4 and cyclin D3/CDK6 cell cycle pathway, with potential antineoplastic activity. CDK4/6 inhibitor LEE011 specifically inhibits CDK4 and 6, thereby inhibiting retinoblastoma (Rb) protein phosphorylation. Inhibition of Rb phosphorylation prevents CDK-mediated G1-S phase transition, thereby arresting the cell cycle in the G1 phase, suppressing DNA synthesis and inhibiting cancer cell growth. Overexpression of CDK4/6, as seen in certain types of cancer, causes cell cycle deregulation. Ribociclib is in phase III clinical trials by Novartis for the treatment of postmenopausal women with advanced breast cancer. Phase II clinical trials are also in development for the treatment of liposarcoma, ovarian cancer, fallopian tube cancer, peritoneum cancer, endometrial cancer, and gastrointestinal cancer. Preregistration for Breast cancer (First-line therapy, Combination therapy, Late-stage disease) in the USA (PO) in November 2016.

Approval Year

Targets

Targets

Primary TargetPharmacologyConditionPotency
10.0 nM [IC50]
154.0 nM [IC50]
39.0 nM [IC50]
126.0 nM [IC50]
Conditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
KISQALI
Primary
PubMed

PubMed

TitleDatePubMed
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
Liver X receptors as regulators of macrophage inflammatory and metabolic pathways.
2011 Aug
Therapeutic response to CDK4/6 inhibition in breast cancer defined by ex vivo analyses of human tumors.
2012 Jul 15
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
A CDK4/6 inhibitor enhances cytotoxicity of paclitaxel in lung adenocarcinoma cells harboring mutant KRAS as well as wild-type KRAS.
2013 Jul
Dual CDK4/CDK6 inhibition induces cell-cycle arrest and senescence in neuroblastoma.
2013 Nov 15
Patents

Sample Use Guides

In Vivo Use Guide
Ribociclib oral (3 weeks on/1 week off) in combination with oral once daily letrozole: 600 mg ribociclib QD + 2.5 mg letrozole QD
Route of Administration: Oral
In Vitro Use Guide
Ribociclib significantly reduced proliferation in 12 of 17 human neuroblastoma-derived cell lines by inducing cytostasis at nanomolar concentrations (mean IC50 of 307 nM in sensitive lines)
Substance Class Chemical
Created
by admin
on Tue Mar 06 11:00:29 UTC 2018
Edited
by admin
on Tue Mar 06 11:00:29 UTC 2018
Record UNII
TK8ERE8P56
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
RIBOCICLIB
INN   USAN   WHO-DD  
INN   USAN  
Official Name English
LEE011
Code English
RIBOCICLIB [INN]
Common Name English
LEE-011A
Code English
RIBOCICLIB [USAN]
Common Name English
7H-PYRROLO(2,3-D)PYRIMIDINE-6-CARBOXAMIDE, 7-CYCLOPENTYL-N,N-DIMETHYL-2-((5-(1-PIPERAZINYL)-2-PYRIDINYL)AMINO)-
Systematic Name English
RIBOCICLIB [WHO-DD]
Common Name English
LEE011A
Code English
LEE-011
Code English
Code System Code Type Description
NCI_THESAURUS
C95701
Created by admin on Tue Mar 06 11:00:29 UTC 2018 , Edited by admin on Tue Mar 06 11:00:29 UTC 2018
PRIMARY
INN
9968
Created by admin on Tue Mar 06 11:00:29 UTC 2018 , Edited by admin on Tue Mar 06 11:00:29 UTC 2018
PRIMARY
EVMPD
SUB180246
Created by admin on Tue Mar 06 11:00:29 UTC 2018 , Edited by admin on Tue Mar 06 11:00:29 UTC 2018
PRIMARY
ChEMBL
CHEMBL3545110
Created by admin on Tue Mar 06 11:00:29 UTC 2018 , Edited by admin on Tue Mar 06 11:00:29 UTC 2018
PRIMARY
WIKIPEDIA
Ribociclib
Created by admin on Tue Mar 06 11:00:29 UTC 2018 , Edited by admin on Tue Mar 06 11:00:29 UTC 2018
PRIMARY
PUBCHEM
44631912
Created by admin on Tue Mar 06 11:00:29 UTC 2018 , Edited by admin on Tue Mar 06 11:00:29 UTC 2018
PRIMARY SWITZERF
CAS
1211441-98-3
Created by admin on Tue Mar 06 11:00:29 UTC 2018 , Edited by admin on Tue Mar 06 11:00:29 UTC 2018
PRIMARY
RXCUI
1873916
Created by admin on Tue Mar 06 11:00:29 UTC 2018 , Edited by admin on Tue Mar 06 11:00:29 UTC 2018
PRIMARY
Related Record Type Details
METABOLIC ENZYME -> INHIBITOR
Ki
EXCRETED UNCHANGED
FECAL
METABOLIC ENZYME -> SUBSTRATE
Coadministration of a strong CYP3A4 inducer (rifampin) decreased the plasma AUC of ribociclib by 89%. The concomitant use of strong CYP3A4 inducers with ribociclib should be avoided.: In a dedicated drug-interaction trial, concomitant ritonavir (a strong CYP3A4 inhibitor) increased a single dose ribociclib’s Cmax by 1.7-fold and the AUC by 3.2-fold.
EXCRETED UNCHANGED
URINE
TRANSPORTER -> INHIBITOR
Ki
TRANSPORTER -> INHIBITOR
Ki
METABOLIC ENZYME -> INHIBITOR
A time-dependent inhibitor (TDI) of CYP3A4/5 (Ki,u: 4.44 μM; kinact: 0.02 min-1 ). In vivo, ribociclib is a CYP3A perpetrator . Ribociclib dosed at 400 mg QD increased the coadministrated midazolam (a sensitive CYP3A4 substrate) AUC by 3.8-fold. Ribociclib given at the recommended dose of 600 mg QD is predicted to increase the midazolam AUC by 5.2-fold.
TIME-DEPENDENT INHIBITION
Ki
BINDER -> LIGAND
BINDING
TARGET -> INHIBITOR
IC50
METABOLIC ENZYME -> INHIBITOR
Ki
TARGET -> INHIBITOR
IC50
Related Record Type Details
ACTIVE MOIETY