RIVICICLIB

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C21H20ClNO5
Molecular Weight	401.84
Optical Activity	UNSPECIFIED
Defined Stereocenters	2 / 2
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CN1CC[C@@H]([C@H]1CO)C2=C3OC(=CC(=O)C3=C(O)C=C2O)C4=C(Cl)C=CC=C4

InChI

InChIKey=QLUYMIVVAYRECT-GXTWGEPZSA-N

InChI=1S/C21H20ClNO5/c1-23-7-6-12(14(23)10-24)19-15(25)8-16(26)20-17(27)9-18(28-21(19)20)11-4-2-3-5-13(11)22/h2-5,8-9,12,14,24-26H,6-7,10H2,1H3/t12-,14+/m0/s1

HIDE SMILES / InChI

Molecular Formula	C21H20ClNO5
Molecular Weight	401.84
Charge	0
Count

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	2 / 2
E/Z Centers	0
Optical Activity	UNSPECIFIED

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/25816934 | https://www.ncbi.nlm.nih.gov/pubmed/17363486 | https://www.ncbi.nlm.nih.gov/pubmed/22873289

P276-00 (also known as riviciclib) is a novel, potent, small-molecule, flavone-derived inhibitor of cyclin-dependent kinases (Cdk), Cdk 4 D1, Cdk1 B, and Cdk9 T, with potent cytotoxic effects against chemosensitive and chemoresistant cancer cell lines. P276-00 was in phase II clinical trial for the treatment mantle cell lymphoma, but that study was terminated based on interim results and all subjects were off study at that time. Although, there were not the major safety or tolerability concerns. However, this drug successfully passed phase II clinical trial for the treatment Melanoma, squamous cell carcinoma of head and neck, malignant melanoma and in combination with Gemcitabine in the treatment of advanced pancreatic cancer.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Cyclin-dependent kinase 4 22 Target ID: P11802 Gene ID: 1019.0 Gene Symbol: CDK4 Target Organism: Homo sapiens (Human) Sources: https://www.ncbi.nlm.nih.gov/pubmed/17363486	Inhibitor 8297	0.063 µM [IC50]
Cyclin-dependent kinase 1 27 Target ID: P06493 Gene ID: 983.0 Gene Symbol: CDK1 Target Organism: Homo sapiens (Human) Sources: https://www.ncbi.nlm.nih.gov/pubmed/17363486	Inhibitor 8297	0.079 µM [IC50]
Cyclin-dependent kinase 9 19 Target ID: P50750 Gene ID: 1025.0 Gene Symbol: CDK9 Target Organism: Homo sapiens (Human) Sources: https://www.ncbi.nlm.nih.gov/pubmed/17363486	Inhibitor 8297	0.02 µM [IC50]
Cyclin-dependent kinase 1 27 Target ID: CHEMBL308 Sources: https://www.ncbi.nlm.nih.gov/pubmed/17363486	Inhibitor 8297	0.079 µM [IC50]
Cyclin-dependent kinase 2 22 Target ID: CHEMBL301 Sources: https://www.ncbi.nlm.nih.gov/pubmed/17363486	Inhibitor 8297	0.224 µM [IC50]
Cyclin-dependent kinase 4 22 Target ID: CHEMBL331 Sources: https://www.ncbi.nlm.nih.gov/pubmed/17363486	Inhibitor 8297	0.063 µM [IC50]
Cyclin-dependent kinase 9 19 Target ID: CHEMBL3116 Sources: https://www.ncbi.nlm.nih.gov/pubmed/17363486	Inhibitor 8297	0.02 µM [IC50]
Cyclin-dependent kinase 6 12 Target ID: CHEMBL2508 Sources: https://www.ncbi.nlm.nih.gov/pubmed/17363486	Inhibitor 8297	0.396 µM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Mantle cell lymphoma 24 Sources: https://www.ncbi.nlm.nih.gov/pubmed/25816934	Primary	Phase II 1132	Unknown Approved Use Unknown
Head and neck squamous cell carcinoma 32 Sources: https://www.ncbi.nlm.nih.gov/pubmed/23414419	Primary	Phase II 1132	Unknown Approved Use Unknown
Pancreatic cancer 97 Sources: https://www.ncbi.nlm.nih.gov/pubmed/22873289	Primary	Phase II 1132	Unknown Approved Use Unknown
Malignant melanoma 22 Sources: https://clinicaltrials.gov/ct2/show/NCT00835419	Primary	Phase II 1132	Unknown Approved Use Unknown

C_max

Value	Dose	Co-administered	Analyte	Population
1818.96 ng/mL EXPERIMENT https://cancerres.aacrjournals.org/content/68/9_Supplement/5079	94.5 mg/m² 1 times / day multiple, intravenous dose: 94.5 mg/m² route of administration: Intravenous experiment type: MULTIPLE co-administered:		RIVICICLIB HYDROCHLORIDE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

AUC

Value	Dose	Co-administered	Analyte	Population
5158.09 ng × h/mL EXPERIMENT https://cancerres.aacrjournals.org/content/68/9_Supplement/5079	94.5 mg/m² 1 times / day multiple, intravenous dose: 94.5 mg/m² route of administration: Intravenous experiment type: MULTIPLE co-administered:		RIVICICLIB HYDROCHLORIDE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

T_1/2

Value	Dose	Co-administered	Analyte	Population
6.22 h EXPERIMENT https://cancerres.aacrjournals.org/content/68/9_Supplement/5079	94.5 mg/m² 1 times / day multiple, intravenous dose: 94.5 mg/m² route of administration: Intravenous experiment type: MULTIPLE co-administered:		RIVICICLIB HYDROCHLORIDE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

Doses

Dose	Population	Adverse events
185 mg/m2 1 times / day multiple, intravenous Recommended Dose: 185 mg/m2, 1 times / day Route: intravenous Route: multiple Dose: 185 mg/m2, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/25816934 Page: p.13	unhealthy, ADULT n = 13 Health Status: unhealthy Condition: mantle cell lymphoma Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 13 Sources: https://pubmed.ncbi.nlm.nih.gov/25816934 Page: p.13	Disc. AE: Herpes zoster... Other AEs: Thrombocytopenia... AEs leading to discontinuation/dose reduction: Herpes zoster (grade 2, 7.7%) Other AEs: Thrombocytopenia (grade 4, 7.7%) Sources: https://pubmed.ncbi.nlm.nih.gov/25816934 Page: p.13

AEs

AE	Significance	Dose	Population
Herpes zoster	grade 2, 7.7% Disc. AE	185 mg/m2 1 times / day multiple, intravenous Recommended Dose: 185 mg/m2, 1 times / day Route: intravenous Route: multiple Dose: 185 mg/m2, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/25816934 Page: p.13	unhealthy, ADULT n = 13 Health Status: unhealthy Condition: mantle cell lymphoma Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 13 Sources: https://pubmed.ncbi.nlm.nih.gov/25816934 Page: p.13
Thrombocytopenia	grade 4, 7.7%	185 mg/m2 1 times / day multiple, intravenous Recommended Dose: 185 mg/m2, 1 times / day Route: intravenous Route: multiple Dose: 185 mg/m2, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/25816934 Page: p.13	unhealthy, ADULT n = 13 Health Status: unhealthy Condition: mantle cell lymphoma Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 13 Sources: https://pubmed.ncbi.nlm.nih.gov/25816934 Page: p.13

Overview

CYP3A4	CYP2C9	CYP2D6	hERG

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
P-gp 1461

Drug as perpetrator

Target	Modality	Activity	Metabolite	Clinical evidence
P-gp 1650	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1346987#sid=377020350	yes [IC50 5.1735 uM]

PubMed

Title	Date	PubMed
In vitro antitumor properties of a novel cyclin-dependent kinase inhibitor, P276-00.	2007 Mar	17363486
P276-00, a novel cyclin-dependent inhibitor induces G1-G2 arrest, shows antitumor activity on cisplatin-resistant cells and significant in vivo efficacy in tumor models.	2007 Mar	17363487
A phase II, single-arm, open-label, multicenter study to evaluate the efficacy and safety of P276-00, a cyclin-dependent kinase inhibitor, in patients with relapsed or refractory mantle cell lymphoma.	2015 Jul	25816934

Patents

Sample Use Guides

In Vivo Use Guide

A phase II study of P276-00 was conducted in patients with relapsed or refractory mantle cell lymphoma (MCL) at the recommended dose of 185 mg/m(2)/day from days 1 to 5 of a 21-day cycle.

Route of Administration: Intravenous

In Vitro Use Guide

P276-00 was found to be more selective with IC50s <100 nmol/L for Cdk4-D1, Cdk1-B, and Cdk9-T1, as compared with other Cdks, and less selective for non-Cdk kinases. It shows potent antiproliferative effects against various human cancer cell lines, including HCT-116, U2OS, H-460, HL-60, HT-29, SiHa, MCF-7, Colo-205, SW-480, PC-3, Caco2, T-24 with an IC50 ranging from 300 to 800 nmol/L, and is found to be highly selective for cancer cells as compared with normal fibroblast cells

Substance Class	Chemical Created by `admin` on `Sat Dec 16 01:42:18 GMT 2023` Edited by `admin` on `Sat Dec 16 01:42:18 GMT 2023`
Record UNII	9EK26WE8QN
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

RIVICICLIB

Official Name

English

(+)-RIVICICLIB

Common Name

English

4H-1-BENZOPYRAN-4-ONE, 2-(2-CHLOROPHENYL)-5,7-DIHYDROXY-8-((2R,3S)-2-(HYDROXYMETHYL)-1-METHYL-3-PYRROLIDINYL)-

Systematic Name

English

Riviciclib [WHO-DD]

Common Name

English

P 276-00 FREE BASE

Code

English

P-276-00 FREE BASE

Code

English

riviciclib [INN]

Common Name

English

Classification Tree Code System Code

NCI_THESAURUS

C2185