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R547 CDK inhibitor

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

R547 CDK inhibitor Chemical Structure

Chemical Structure

Molecular Weight: 441.45

Purity & Quality Control

Related Products

Signaling Pathway

CDK Signaling Pathways

CDK Signaling Pathway

Mechanism of Action

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
In vitro R547 identified as a diaminopyrimidine compound, which is a potent and selective ATP-competitive CDK inhibitor. This compound 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. It 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. This chemical 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. It 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] This inhibitor 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
In vivo R547 administered with oral and i.v. dosing in multiple established human tumor significantly inhibits tumor activity(P < 0.01). This compound 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%). It is equally efficacious (TGI, 61-95%) when dosed with 40 mg/kg i.v. once weekly. These doses of this chemical are not toxic and did not result in body weight loss. It 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] This compound inhibits tumor growth up to 95% in the HCT116 human colorectal tumor xenograft model in nude mice . It causes significant TGI in all of the models tested when dosed orally and i.v. at or below the maximum tolerated dose. It inhibits phosphorylation of retinoblastoma protein in tumors at the efficacious exposures in tumor xenograft models, providing a pharmacodynamic biomarker for clinical use. This molecule reported here suggests that this is a promising molecule for evaluation in the treatment of solid tumors. [2]
Animal Research 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
NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT00400296 Completed
Neoplasms
Hoffmann-La Roche
 May 2005 Phase 1

References
  • https://pubmed.ncbi.nlm.nih.gov/17121911/
  • https://pubmed.ncbi.nlm.nih.gov/17064073/
  • https://pubmed.ncbi.nlm.nih.gov/19755512/

Chemical Information

Molecular Weight 441.45 Formula

C18H21F2N5O4S
CAS No. 741713-40-6 SDF Download SDF
Synonyms Ro 4584820
Smiles COC1=C(C(=C(C=C1)F)F)C(=O)C2=CN=C(N=C2N)NC3CCN(CC3)S(=O)(=O)C

Storage and Stability

Storage (From the date of receipt)

In vitro
Batch:

DMSO : 88 mg/mL ( (199.34 mM) Moisture-absorbing DMSO reduces solubility. Please use fresh DMSO.)

Water : Insoluble

Ethanol : Insoluble


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In vivo
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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.

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