R547

Catalog No.S2688 Synonyms: Ro 4584820

For research use only.

R547 (Ro 4584820) is a potent ATP-competitive inhibitor of CDK1/2/4 with Ki of 2 nM/3 nM/1 nM. It is less potent to CDK7 and GSK3α/β, while inactive to other kinases. Phase 1.

R547 Chemical Structure

CAS No. 741713-40-6

Selleck's R547 has been cited by 4 Publications

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Biological Activity

Description R547 (Ro 4584820) is a potent ATP-competitive inhibitor of CDK1/2/4 with Ki of 2 nM/3 nM/1 nM. It is less potent to CDK7 and GSK3α/β, while inactive to other kinases. Phase 1.
Targets
CDK4/CyclinD1 [1]
(Cell-free assay)
CDK1/CyclinB [1]
(Cell-free assay)
CDK2/CyclinE [1]
(Cell-free assay)
1 nM(Ki) 2 nM(Ki) 3 nM(Ki)
In vitro

R547 identified as a diaminopyrimidine compound, which is a potent and selective ATP-competitive CDK inhibitor. R547 effectively inhibits CDK1/cyclinB, CDK2/cyclinE, and CDK4/cyclinD1(Ki=1-3nM) and is inactive(Ki>5,000nM) against a panel of >120 unrelated kinases. R547 effectively inhibits the proliferation of tumor cell lines independent of multidrug resistant status, histologic type, retinoblastoma protein, or p53 status, with IC50s <0.60 μM. R547 reduces phosphorylation of the cellular retinoblastoma protein at specific CDK phosphorylation sites at the same concentrations that induced cell cycle arrest, suggesting a potential pharmaco dynamics marker for clinical use. R547 inhibits the proliferation of tumor cell lines and is active in all 19 cell lines tested irrespective of tissue of origin, multidrug resistance (MDR), p53, or retinoblastoma status. [1] R547 possessing both 5-and 6-fluoro substitution culminated in an Inhibitor with low, single-digit nanomolar potency against the CDKs(Ki=0.001,0.003,and 0.001 μM for CDK1,CDK2, and CDK4,respectively) and excellent cellular potency (IC50=0.08 μM,HCT116 cell line). [2]

In vivo R547 administered with oral and i.v. dosing in multiple established human tumor significantly inhibits tumor activity(P < 0.01). R547 administered orally at dose of 40 mg/kg daily in colon, lung, breast, prostate, and melanoma human tumor xenograft models shows significant TGI (79-99%). R547 is equally efficacious (TGI, 61-95%) when dosed with 40 mg/kg i.v. once weekly. These doses of R547 are not toxic and did not result in body weight loss. R547 does not show signs of overt toxicity during the course of the 3-week study and any gross pathology at necropsies done at the end of the studies. [1] R547 inhibits tumor growth up to 95% in the HCT116 human colorectal tumor xenograft model in nude mice . R547 causes significant TGI in all of the models tested when dosed orally and i.v. at or below the maximum tolerated dose. R547 inhibits phosphorylation of retinoblastoma protein in tumors at the efficacious exposures in tumor xenograft models, providing a pharmacodynamic biomarker for clinical use. R547 reported here suggests that this is a promising molecule for evaluation in the treatment of solid tumors. [2]

Protocol (from reference)

Animal Research:

[2]

  • Animal Models: female nude mice bearing established HCT116 human colorectal xenografts with a mean starting volume of about 100 mm3
  • Dosages: 25 ,50,75 mg/kg
  • Administration: Orally three times per week on Monday, Wednesday, and Friday for 18days

Solubility (25°C)

In vitro

DMSO 60 mg/mL
(135.91 mM)
Water Insoluble
Ethanol Insoluble

In vivo

Add solvents to the product individually and in order
(Data is from Selleck tests instead of citations):
1% hydroxyethyl cellulose+0.2% Tween 80
For best results, use promptly after mixing.

30 mg/mL

Chemical Information

Molecular Weight 441.45
Formula

C18H21F2N5O4S

CAS No. 741713-40-6
Storage 3 years -20°C powder
2 years -80°C in solvent
Smiles COC1=C(C(=C(C=C1)F)F)C(=O)C2=CN=C(N=C2N)NC3CCN(CC3)S(=O)(=O)C

In vivo Formulation Calculator (Clear solution)

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Method for preparing DMSO master liquid: mg drug pre-dissolved in μL DMSO ( Master liquid concentration mg/mL, Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug. )

Method for preparing in vivo formulation: Take μL DMSO master liquid, next addμL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O, mix and clarify.

Method for preparing in vivo formulation: Take μL DMSO master liquid, next add μL Corn oil, mix and clarify.

Note: 1. Please make sure the liquid is clear before adding the next solvent.
2. Be sure to add the solvent(s) in order. You must ensure that the solution obtained, in the previous addition, is a clear solution before proceeding to add the next solvent. Physical methods such
as vortex, ultrasound or hot water bath can be used to aid dissolving.

Molarity Calculator

Mass Concentration Volume Molecular Weight

Clinical Trial Information

NCT Number Recruitment Interventions Conditions Sponsor/Collaborators Start Date Phases
NCT00400296 Completed Drug: RG547 Neoplasms Hoffmann-La Roche May 2005 Phase 1

(data from https://clinicaltrials.gov, updated on 2022-01-17)

Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

Handling Instructions

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