RKI-1447

Potent ROCK1/ROCK2 inhibitor CAS# 1342278-01-6

RKI-1447

Catalog No. BCC1903----Order now to get a substantial discount!

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Chemical structure

RKI-1447

3D structure

Chemical Properties of RKI-1447

Cas No. 1342278-01-6 SDF Download SDF
PubChem ID 60138149 Appearance Powder
Formula C16H14N4O2S M.Wt 326.37
Type of Compound N/A Storage Desiccate at -20°C
Solubility DMSO : ≥ 50 mg/mL (153.20 mM)
H2O : < 0.1 mg/mL (insoluble)
*"≥" means soluble, but saturation unknown.
Chemical Name 1-[(3-hydroxyphenyl)methyl]-3-(4-pyridin-4-yl-1,3-thiazol-2-yl)urea
SMILES C1=CC(=CC(=C1)O)CNC(=O)NC2=NC(=CS2)C3=CC=NC=C3
Standard InChIKey GDVRVPIXWXOKQO-UHFFFAOYSA-N
Standard InChI InChI=1S/C16H14N4O2S/c21-13-3-1-2-11(8-13)9-18-15(22)20-16-19-14(10-23-16)12-4-6-17-7-5-12/h1-8,10,21H,9H2,(H2,18,19,20,22)
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of RKI-1447

DescriptionRKI-1447 is a potent inhibitor of ROCK1 and ROCK2 with IC50 values of 14.5 nM and 6.2 nM, respectively.
TargetsROCK1ROCK2    
IC5014.5 nM6.2 nM    

Protocol

Kinase Assay [1]
Compounds are tested on three separate days with 8 point dilutions performed in duplicate to determine average IC50 values. The assay conditions are optimized to 15 µL of kinase reaction volume with 5 ng of enzyme in 50 mM HEPES (pH 7.5), 10 mM MgCl2, 1 mM EGTA, and 0.01% Brij-35. The reaction is incubated for 1 h at room temperature in the presence of 1.5 µM of peptide substrate with 12.5 µM of ATP (for ROCK1) or 2 µM of substrate with 50 µM of ATP (for ROCK2). The reaction is then stopped and the ratio of phosphorylated to unphosphorylated peptides is determined by selective cleavage of only the unphosphorylated peptide. The ratio of the signals at 445 nm and 520 nm is measured. IC50 values are determined using fitted curves with GraphPad Prism 5 software[1].

Cell Assay [1]
NIH 3T3 cells are plated at 8000 cells/well in 8-chamber slides in serum free media for 24 hours, and treated with vehicle, 1 μM RKI-1447 or 1 μM RKI-1313 for 1 hour. The cells are then stimulated with complete media, 10 μM LPA, 200 ng/mL bradykinin or 30 ng/mL PDGF for 30 mins. After stimulation, the cells are fixed in 4% paraformaldehyde and stained with Texas-Red Phalloidin. Mounting medium containing DAPI is then added and at least 100 cells per well are observed[1].

Animal Administration [1]
Mice: MMTV/neu transgenic mice are treated i.p. daily for 14 days with either Vehicle [20%-2-hydroxypropyl-beta-cyclodextrin (HPCD)] or 200 mpk RKI-1447 dissolved in freshly prepared HPCD. The percent change in volume is calculated on the basis of the tumor volume on the last day of treatment (Vf) relative to that on the day of initiation of treatment (V0). The average percent change in tumor volume is then calculated for each treatment group[1].

References:
[1]. Patel RA, et al. RKI-1447 is a potent inhibitor of the Rho-associated ROCK kinases with anti-invasive and antitumor activities in breast cancer. Cancer Res. 2012 Oct 1;72(19):5025-34.

RKI-1447 Dilution Calculator

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RKI-1447 Molarity Calculator

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Preparing Stock Solutions of RKI-1447

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 3.064 mL 15.32 mL 30.6401 mL 61.2801 mL 76.6002 mL
5 mM 0.6128 mL 3.064 mL 6.128 mL 12.256 mL 15.32 mL
10 mM 0.3064 mL 1.532 mL 3.064 mL 6.128 mL 7.66 mL
50 mM 0.0613 mL 0.3064 mL 0.6128 mL 1.2256 mL 1.532 mL
100 mM 0.0306 mL 0.1532 mL 0.3064 mL 0.6128 mL 0.766 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on RKI-1447

RKI-1447 is a potent inhibitor of ROCK 1 and 2 (Rho-associated protein kinase 1 and 2).

ROCK is a serine-threonine kinase, which regulates cell shape and movement via acting on cytoskeleton.

RKI-1447 specifically and dose-dependently inhibits ROCK1 and ROCK2. RKI-1447 inhibited the phosphorylation of the ROCK substrates MLC-2 and MYPT-1 in human cancer cells. However, it does not affect the phosphorylation of the AKT, MEK, and S6 kinase at a high concentrations of 10 μmol/L. It indicated a high specificity. Additionally, it was also observed that RKI-1447 selectively suppressed ROCK-mediated cytoskeleton re-organization following LPA stimulation, but does not affect PAK-meditated lamellipodia and filopodia formation following PDGF and Bradykinin stimulation. RKI-1447 inhibited migration, invasion and anchorage-independent tumor growth of breast cancer cells [1]

In mouse model, tumors were monitored at the time of tumor onset and the beginning of treatment (once a day for 14 days) with vehicle (20% HPCD) or RKI-1447 (200 mg/kg/day), when tumor volumes reached 75 to 2,300 mm3. Tumors from mice treated with vehicle increased in average tumor volume of 68.3% but tumors from mice treated with the RKI-1447 increased in average tumor volume of only 8.8%. Thus, RKI-1447 inhibited mammary tumor growth by 87% [1].

Reference:
[1] Patel R A et al. , RKI-1447 Is a Potent Inhibitor of the Rho-Associated ROCK Kinases with Anti-Invasive and Antitumor Activities in Breast Cancer. Cancer Res, 2012, 72(19): 5025-5034.

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References on RKI-1447

RKI-1447 is a potent inhibitor of the Rho-associated ROCK kinases with anti-invasive and antitumor activities in breast cancer.[Pubmed:22846914]

Cancer Res. 2012 Oct 1;72(19):5025-34.

The Rho-associated kinases ROCK1 and ROCK2 are critical for cancer cell migration and invasion, suggesting they may be useful therapeutic targets. In this study, we describe the discovery and development of RKI-1447, a potent small molecule inhibitor of ROCK1 and ROCK2. Crystal structures of the RKI-1447/ROCK1 complex revealed that RKI-1447 is a Type I kinase inhibitor that binds the ATP binding site through interactions with the hinge region and the DFG motif. RKI-1447 suppressed phosphorylation of the ROCK substrates MLC-2 and MYPT-1 in human cancer cells, but had no effect on the phosphorylation levels of the AKT, MEK, and S6 kinase at concentrations as high as 10 mumol/L. RKI-1447 was also highly selective at inhibiting ROCK-mediated cytoskeleton re-organization (actin stress fiber formation) following LPA stimulation, but does not affect PAK-meditated lamellipodia and filopodia formation following PDGF and Bradykinin stimulation, respectively. RKI-1447 inhibited migration, invasion and anchorage-independent tumor growth of breast cancer cells. In contrast, RKI-1313, a much weaker analog in vitro, had little effect on the phosphorylation levels of ROCK substrates, migration, invasion or anchorage-independent growth. Finally, RKI-1447 was highly effective at inhibiting the outgrowth of mammary tumors in a transgenic mouse model. In summary, our findings establish RKI-1447 as a potent and selective ROCK inhibitor with significant anti-invasive and antitumor activities and offer a preclinical proof-of-concept that justify further examination of RKI-1447 suitability as a potential clinical candidate.

Description

RKI-1447 is a potent small molecule inhibitor of ROCK1 and ROCK2 with IC50 values of 14.5 nM and 6.2 nM, respectively.

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