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R547 (R-547; Ro4584820; R 547; Ro-4584820) is a potent, selective and ATP-competitive inhibitor of CDK1/2/4 with potential antitumor activity. R547 exhibits lower potency or inactivity against CDK7, GSK3α/β, and additional kinases. R547 is effective against all 19 cell lines tested, regardless of tissue of origin, multidrug resistance (MDR), p53, or retinoblastoma status. It also inhibits the proliferation of tumor cell lines. An inhibitor with low, single-digit nanomolar potency against the CDKs and excellent cellular potency (IC50=0.08 μM, HCT116 cell line) was produced by R547, which possessed both 5- and 6-fluoro substitution.
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Physicochemical Properties
| Molecular Formula |
C18H21F2N5O4S
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| Molecular Weight |
441.45
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| Exact Mass |
441.128
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| Elemental Analysis |
C, 48.97; H, 4.79; F, 8.61; N, 15.86; O, 14.50; S, 7.26
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| CAS # |
741713-40-6
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| Related CAS # |
869369-26-6 (mesylate);741713-40-6;
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| PubChem CID |
6918852
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| Appearance |
White to off-white solid powder
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| Density |
1.49
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| Boiling Point |
703.7ºC at 760 mmHg
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| Flash Point |
379.4ºC
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| Index of Refraction |
1.62
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| LogP |
3.085
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
11
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
30
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| Complexity |
701
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O=S(N1CCC(NC2=NC(N)=C(C(C3=C(C(F)=CC=C3OC)F)=O)C=N2)CC1)(C)=O
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| InChi Key |
JRNJNYBQQYBCLE-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C18H21F2N5O4S/c1-29-13-4-3-12(19)15(20)14(13)16(26)11-9-22-18(24-17(11)21)23-10-5-7-25(8-6-10)30(2,27)28/h3-4,9-10H,5-8H2,1-2H3,(H3,21,22,23,24)
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| Chemical Name |
[4-amino-2-[(1-methylsulfonylpiperidin-4-yl)amino]pyrimidin-5-yl]-(2,3-difluoro-6-methoxyphenyl)methanone
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| Synonyms |
| R547; Ro4584820; R 547; Ro-4584820; R-547; Ro 4584820 |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder-20°C 3 years
4°C 2 years
In solvent -80°C 6 months
-20°C 1 month
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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Biological Activity
| Targets |
Cdk1/cyclin B (Ki = 2 nM); CDK2/cyclinE (Ki = 3 nM); CDK4/cyclin D (Ki = 1 nM); cdk2/cyclin A (IC50 = 0.1 nM); CDK2/cyclinE (IC50 = 0.4 nM); Cdk1/cyclin B (IC50 = 0.2 nM); CDK3/Cyclin E (IC50 = 0.8 nM); CDK5/p35 (IC50 = 0.1 nM); cdk6/cyclin D3 (IC50 = 4 nM); CDK7/cyclin H (IC50 = 171 nM); GSK-3α (IC50 = 46 nM); GSK-3β (IC50 = 260 nM)
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| ln Vitro |
R547 was discovered to be a diaminopyrimidine compound, a strong and particular CDK inhibitor that competes with ATP. In a panel of more than 120 unrelated kinases, R547 is inactive (Ki>5,000nM) and effectively inhibits CDK1/cyclinB, CDK2/cyclinE, and CDK4/cyclinD1 (Ki=1-3nM). Regardless of the histologic type, p53 status, retinoblastoma protein, or multidrug resistance, R547 efficiently suppresses the growth of tumor cell lines, with IC50s <0.60 ΖM. The phosphorylation of the cellular retinoblastoma protein is reduced by R547 at particular CDK phosphorylation sites at concentrations that cause cell cycle arrest, indicating that R547 may be a useful pharmacodynamic marker in clinical settings. Regardless of the tissue of origin, p53, multidrug resistance (MDR), or retinoblastoma status, R547 can inhibit the growth of tumor cell lines and is effective in all 19 cell lines tested.[1] The combination of 5-and 6-fluoro substitution in R547 resulted in an inhibitor with excellent cellular potency (IC50=0.08 μM, HCT116 cell line) and low, single-digit nanomolar potency against the CDKs (Ki=0.001,0.003, and 0.001 μM for CDK1, CDK2, and CDK4, respectively). [2] |
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| ln Vivo |
| R547 administered with oral and i.v. dosing in multiple established human tumor significantly inhibits tumor activity(P < 0.01). Human tumor xenograft models for colon, lung, breast, prostate, and melanoma exhibit significant TGI (79–99%) when R547 is given orally at a dose of 40 mg/kg daily. Once weekly, a dose of 40 mg/kg intravenously (i.v.) is equally effective (TGI, 61-95%) for R549. Both the toxicity and the lack of weight loss were observed at these R547 dosages. Neither during the three-week study period nor at the time of the final necropsies, does R547 exhibit any overt toxicity symptoms or gross pathology.[1] R547 inactivates tumor growth in the HCT116 human colorectal tumor xenograft model in nude mice by up to 95%. When administered orally and intravenously (IV) at or below the maximum tolerated dose, R547 significantly increases the risk of TGI in every model examined. R547 provides a pharmacodynamic biomarker for clinical application by inhibiting the phosphorylation of retinoblastoma protein in tumors at the effective exposures in tumor xenograft models. The information provided about R547 indicates that this is a potentially useful compound to investigate for the treatment of solid tumors.[2] |
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| Enzyme Assay |
R547 is a potent ATP-competitive inhibitor of CDK1/2/4 with Ki of 2 nM/3 nM/1 nM.
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| Cell Assay |
R547 is inactive (Ki>5,000nM) against a panel of more than 120 unrelated kinases, but it effectively inhibits CDK1/cyclinB, CDK2/cyclinE, and CDK4/cyclinD1 (Ki=1-3nM). With IC50s<0.60 μM, R547 potently suppresses tumor cell line proliferation, regardless of p53 status, histologic type, retinoblastoma protein, or multidrug resistance. At the same concentrations that cause cell cycle arrest, R547 decreases the phosphorylation of the cellular retinoblastoma protein at particular CDK phosphorylation sites, indicating that it may be a useful pharmacodynamic marker for clinical applications. R547 is effective against all 19 cell lines tested and inhibits the growth of tumor cell lines, regardless of the tissue of origin, p53, multidrug resistance (MDR), or retinoblastoma status. The combination of 5- and 6-fluoro substitution in R547 resulted in an inhibitor with excellent cellular potency (IC50=0.08 μM, HCT116 cell line) and low, single-digit nanomolar potency against the CDKs (Ki=0.001,0.003, and 0.001 μM for CDK1, CDK2, and CDK4, respectively).
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| Animal Protocol |
| sSspended in 1% Klucel LF in water with 0.1% Tween 80; 25 ,50,75 mg/kg; p.o. | | Female nude mice bearing established HCT116 human colorectal xenografts with a mean starting volume of about 100 mm3 | |
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| References |
[1]. Mol Cancer Ther
. 2006 Nov;5(11):2644-58.
[2]. J Med Chem
. 2006 Nov 2;49(22):6549-60.
[3]. Mol Cancer Ther
. 2009 Sep;8(9):2517-25.
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| Additional Infomation |
CDK Inhibitor R547 is an orally bioavailable diaminopyrimidine compound and a cyclin-dependent kinase (CDK) inhibitor with potential antineoplastic activity. CDKs are ATP-dependent serine/threonine kinases that are important regulators of cell cycle progression and are frequently overexpressed in cancerous cells. R547 selectively binds to and inhibits CDKs, especially CDK1/cyclin B, CDK2/cyclin E, and CDK4/cyclin D1. The inhibition of CDKs results in cell cycle arrest, inhibition of tumor cell proliferation, and induction of apoptosis. By inhibiting CDK activity, R547 also reduces phosphorylation of the retinoblastoma (Rb) protein, thereby preventing activation of transcription factor E2F and leading to further suppression of tumor cell proliferation.
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Solubility Data
| Solubility (In Vitro) |
| DMSO: ~60 mg/mL (~135.9 mM) | | Water: <1 mg/mL | | Ethanol: <1 mg/mL |
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| Solubility (In Vivo) |
| 1% hydroxyethyl cellulose+0.2%Tween 80: 30 mg/mL |
(Please use freshly prepared in vivo formulations for optimal results.)
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| Preparing Stock Solutions |
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1 mg |
5 mg |
10 mg |
| 1 mM |
2.2653 mL |
11.3263 mL |
22.6526 mL |
| 5 mM |
0.4531 mL |
2.2653 mL |
4.5305 mL |
| 10 mM |
0.2265 mL |
1.1326 mL |
2.2653 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles. |
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