RIBOCICLIB HYDROCHLORIDE

Details

Stereochemistry	ACHIRAL
Molecular Formula	C23H30N8O.ClH
Molecular Weight	470.998
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

SMILES

Cl.CN(C)C(=O)C1=CC2=CN=C(NC3=CC=C(C=N3)N4CCNCC4)N=C2N1C5CCCC5

InChI

InChIKey=JZRSIQPIKASMEV-UHFFFAOYSA-N

InChI=1S/C23H30N8O.ClH/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);1H

HIDE SMILES / InChI

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.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
IMR-5 3	Inhibitor 8,297	126.0 nM [IC50]
SH-SY5Y 3	Inhibitor 8,297	154.0 nM [IC50]
Cyclin-dependent kinase 4 22	Inhibitor 8,297	10.0 nM [IC50]
Cyclin-dependent kinase 6 12	Inhibitor 8,297	39.0 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
(HER2)-negative advanced or metastatic breast cancer 3	Primary		Approved 8,429	KISQALI
Breast cancer 434	Primary		Phase III 656	Unknown

C_max

Value	Dose	Co-administered	Analyte	Population
1168 ng/mL	600 mg 1 times / day multiple, oral	LETROZOLE	RIBOCICLIB plasma	Homo sapiens

AUC

Value	Dose	Co-administered	Analyte	Population
4714 ng × h/mL	600 mg 1 times / day multiple, oral	LETROZOLE	RIBOCICLIB plasma	Homo sapiens

T_1/2

Value	Dose	Co-administered	Analyte	Population
30 h	600 mg 1 times / day multiple, oral	LETROZOLE	RIBOCICLIB plasma	Homo sapiens

F_unbound

Value	Dose	Co-administered	Analyte	Population
30%			RIBOCICLIB plasma	Homo sapiens

Doses

Show entries

Dose	Population	Adverse events
280 mg/m2 1 times / day steady, oral	unhealthy, 2.0 years (range: 1.0–17.0) n = 5	DLT: Fatigue...
900 mg 1 times / day multiple, oral MTD	unhealthy, 49 years (range: 31-66 years) n = 12
400 mg 1 times / day steady, oral	unhealthy, 57.0 years (range: 33–73 years) n = 4	DLT: Febrile neutropenia...
600 mg 1 times / day steady, oral	unhealthy, 57.0 years (range: 33–73 years) n = 13	DLT: Febrile neutropenia, QT interval prolonged...
470 mg/m2 1 times / day steady, oral MTD	unhealthy, 7.0 years (range: 1.0–20.0 years) n = 12	DLT: Thrombocytopenia... Other AEs: Neutropenia, Leukopenia...

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AEs

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AE	Significance	Dose	Population
Fatigue	grade 3, 1 patient DLT	280 mg/m2 1 times / day steady, oral	unhealthy, 2.0 years (range: 1.0–17.0) n = 5
Febrile neutropenia	grade 3, 1 patient DLT	400 mg 1 times / day steady, oral	unhealthy, 57.0 years (range: 33–73 years) n = 4
Febrile neutropenia	grade 3, 1 patient DLT	600 mg 1 times / day steady, oral	unhealthy, 57.0 years (range: 33–73 years) n = 13
QT interval prolonged	grade 3, 2 patients DLT	600 mg 1 times / day steady, oral	unhealthy, 57.0 years (range: 33–73 years) n = 13
Neutropenia	grade 4, 1 patient DLT	600 mg 1 times / day steady, oral	unhealthy, 57.0 years (range: 33–73 years) n = 13

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Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1,737	substrate 1,037	substrate 1,217	inhibitor 1,612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
Nav1.5 97 Cav1.2 45 CYP3A 214 CYP1A2 1,524 CYP2E1 882 CYP3A4/5 278 BCRP 699 OCT2 647 MATE1 306 BSEP 402	FMO3 67 BCRP 561 P-gp 1,537 CYP1A2 1,054 CYP2J2 56 CYP3A5 395 CYP2A6 543 CYP2B6 664 CYP2C8 693 CYP2C18 138 CYP2C19 991 CYP2E1 667

Drug as perpetrator

Show entries

Target	Modality	Activity	Clinical evidence
MATE1 308	inhibitor 3,277	yes [Ki 1.7 uM]
OCT2 648	inhibitor 3,277	yes [Ki 1.9 uM]
CYP1A2 1,692	inhibitor 3,277	yes [Ki 13 uM]	no (co-administration study)
BCRP 773	inhibitor 3,277	yes [Ki 24 uM]
CYP2E1 970	inhibitor 3,277	yes [Ki 24.5 uM]

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Drug as victim

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Target	Modality	Activity
CYP1A2 1,054	substrate 3,367	minor
CYP2J2 56	substrate 3,367	minor
CYP3A5 395	substrate 3,367	minor
CYP2A6 543	substrate 3,367	no
CYP2B6 664	substrate 3,367	no

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Tox targets

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Target	Modality	Metabolite
Cav1.2 49	inhibitor 1,626
Nav1.5 100	inhibitor 1,626
hERG 1,647	inhibitor 1,626
hERG 1,647	inhibitor 1,626	LEQ803 3

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Sourcing

Sourcing

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Vendor/Aggregator	ID	URL
AA Blocks	AA003A9C	https://www.aablocks.com/goods/Goods/detail?id=AA003A9C
AK Scientific, Inc. (AKSCI)	2513AH	http://www.aksci.com/item_detail.php?cat=2513AH
AK Scientific, Inc. (AKSCI)	SYN1213	http://www.aksci.com/item_detail.php?cat=SYN1213
Aaron Chemicals	AR003B14	http://www.aaronchem.com/1211441-98-3
Achemo Scientific Limited	AC-92785	http://www.achemo.com/search/?Keyword=1211441-98-3

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PubMed

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Title	Date	PubMed
Liver X receptors as regulators of macrophage inflammatory and metabolic pathways.	2011 Aug	21193033
Therapeutic targeting of the cyclin D3:CDK4/6 complex in T cell leukemia.	2012 Oct 16	23079656

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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)

Show entries

Name

Type

Language

RIBOCICLIB HYDROCHLORIDE

Common Name

English

7H-PYRROLO(2,3-D)PYRIMIDINE-6-CARBOXAMIDE, 7-CYCLOPENTYL-N,N-DIMETHYL-2-((5-(1-PIPERAZINYL)-2-PYRIDINYL)AMINO)-, HYDROCHLORIDE (1:1)

Systematic Name

English

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Code System

Code

Type

Description

DRUG BANK

DBSALT002059

PRIMARY

FDA UNII

63YF7YKW7E

PRIMARY

PUBCHEM

67242274

PRIMARY

CAS

1211443-80-9

PRIMARY

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ACTIVE MOIETY


					TK8ERE8P56

RIBOCICLIB

SUBSTANCE RECORD


					63YF7YKW7E

RIBOCICLIB HYDROCHLORIDE

SMILES

InChI

Originator

Approval Year

Targets

Conditions

Cmax

AUC

T1/2

Funbound

Doses

AEs

Overview

OverviewOther

Drug as perpetrator​

Drug as victim

Tox targets

Sourcing

PubMed

Patents

Sample Use Guides

C_max

T_1/2

F_unbound

Drug as perpetrator