Home Cell Cycle CDK inhibitor - Apoptosis related activator Riviciclib hydrochloride (P276-00)

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Riviciclib hydrochloride (P276-00) CDK inhibitor

Cat.No.S8058

Riviciclib hydrochloride (P276-00) is a novel CDK1, CDK4 and CDK9 inhibitor with IC50 of 79 nM, 63 nM and 20 nM, respectively. This compound induces apoptosis. Phase 2/3.
Riviciclib hydrochloride (P276-00) CDK inhibitor Chemical Structure

Chemical Structure

Molecular Weight: 438.3

Jump to Mechanism of Action Cell Culture & Working Concentration Solubility Chemical Information, Storage & Stability Specificity

Quality Control

Batch: S805801 DMSO]88 mg/mL]false]Water]88 mg/mL]false]Ethanol]7 mg/mL]false Purity: 99.26%
99.26

Cell Culture, Treatment & Working Concentration

Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
KB-8-5-11 qHTS assay P-glycoprotein substrates identified in KB-8-5-11 adenocarcinoma cell line, qHTS therapeutic library screen, Potency = 5.1735 μM. 31515284
KB-3-1 qHTS assay P-glycoprotein substrates identified in KB-3-1 adenocarcinoma cell line, qHTS therapeutic library screen. 31515284
Click to View More Cell Line Experimental Data

Chemical Information, Storage & Stability

Molecular Weight 438.3 Formula

C21H20ClNO5.HCl

 Storage (From the date of receipt)
CAS No. 920113-03-7 Download SDF Storage of Stock Solutions

Synonyms N/A Smiles CN1CCC(C1CO)C2=C(C=C(C3=C2OC(=CC3=O)C4=CC=CC=C4Cl)O)O.Cl

Solubility

In vitro
Batch:

DMSO : 88 mg/mL (200.77 mM)
(Moisture-contaminated DMSO may reduce solubility. Use fresh, anhydrous DMSO.)

Water : 88 mg/mL

Ethanol : 7 mg/mL

Molarity Calculator

Mass Concentration Volume Molecular Weight

In vivo
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Mechanism of Action

Targets/IC50/Ki
CDK9/CyclinT1 [1]
20 nM
CDK4/CyclinD1 [1]
63 nM
CDK1/CyclinB [1]
79 nM
CDK2/CyclinA [1]
224 nM
CDK6/CyclinD3 [1]
396 nM
CDK2/CyclinE [1]
2.54 μM
GSK-3β [1]
2.771 μM
CDK7/CyclinH [1]
2.87 μM
In vitro
P276-00 shows 40-fold selectivity toward Cdk4-D1, compared with Cdk2-E[1]. 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[1]. This compound can down-regulate cyclin D1 and Cdk4 in an ATP- competitive manner and decrease Cdk4-specific pRb Ser780 phosphorylation. It also induces apoptosis by actving cellular caspase-3 activity and DNA ladder formation[1].
Kinase Assay
Cdk4-D1/Cdk2-E enzyme assay
The Cdk4-D1/Cdk2-E enzyme assay is run in 96-well format using Millipore Multiscreen filtration plates. All assay steps are done in a single filter plate. The filtration wells are prewetted with 100 μL of kinase buffer [50 mmol/L HEPES (pH, 7.5), 10 mmol/L MgCl2, 1 mmol/L EGTA], and then the solution is removed by vacuum. With filter plate on vacuum manifold, 50 μL GST-Rb bound to GSH-Sepharose beads in kinase buffer (0.5 μg GST-Rb/50 μL) is added to each well, and vacuum is applied to the filter plate. About 25 μL of a reaction mix containing ATP (cold + hot) and 4× phosphatase inhibitor mix (40 μmol/L unlabeled ATP, 10 μCi/mL γ32P-ATP, 40 mmol/L h-glycerophosphate, 4 mmol/L DTT, 0.4 mmol/L NaF, 0.4 mmol/L sodium orthovanadate) diluted in kinase buffer is added to each well. The test compound (4×final concentration in kinase buffer) or kinase buffer alone (control) is then added in an additional 25 μL volume. To each well, 50 μL (100 ng) of human Cdk4-D1/Cdk2-E enzyme in kinase buffer is added to initiate the reaction, which is allowed to continue for 30 min at 30°C. When the reaction is completed, vacuum is applied again, and the plate is washed with the TNEN buffer [20 mmol/L Tris (pH, 8.0), 100 mmol/L NaCl, 1 mmol/L EDTA, 0.5% nonidet-P40] thrice; the filter plate is air-dried and is placed in a Multiscreen adapter plate. Packard Microscint-O cocktail (30 μL) is added, and the plate is covered with a Top-Seal A film. Quantitation of 32P-GST-Rb in 96-well filter plates is carried out by Top Count scintillation counter. All compounds are tested initially at 1 μmol/L concentration. Compounds showing more than or equal to 50% inhibition are further profiled for IC50 determination.
In vivo
P276-00, administered i.p. at 50 mg/kg daily for 20 treatments can significantly induce growth inhibition of murine colon cancer (CA-51). However, in murine lung carcinoma model (Lewis lung), an increased dose of 60 mg/kg (30 mg/kg twice daily) administered every alternate day i.p. for 7 treatments shows significant inhibition in the growth[2]. And this compound also inhibit the growth of human colon carcinoma HCT-116 xenograft and human non-small cell lung carcinoma H-460 xenograft[2]. Efficacy Studies show its maximum tolerated dose is 78 mg/kg/d[2].
References

Clinical Trial Information

(data from https://clinicaltrials.gov, updated on 2024-05-22)

NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT00899054 Completed
Squamous Cell Carcinoma of Head and Neck
Piramal Enterprises Limited
 August 2009 Phase 1|Phase 2
NCT00898287 Completed
Pancreatic Cancer
Piramal Enterprises Limited
 May 2009 Phase 1|Phase 2
NCT00547404 Withdrawn
Multiple Myeloma
Piramal Enterprises Limited
 December 2008 Phase 1
NCT00882063 Completed
Relapsed and/or Refractory Multiple Myeloma
Piramal Enterprises Limited
 January 2008 Phase 1|Phase 2
NCT00407498 Completed
Neoplasm
Piramal Enterprises Limited
 May 2005 Phase 1

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