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Purity: ≥98%
KRN 633 (KRN-633) is a novel, potent, selective, cell-permeable, reversible, and ATP-competitive inhibitor of VEGFR1/2/3 with potential antitumor activity. It does not prevent the phosphorylation of FGFR-1, EGFR, or c-Met in cells, but it weakly inhibits PDGFR-α/β and c-Kit. Its IC50s for VEGFR1/2/3 are 170 nM, 160 nM, and 125 nM. In a number of in vivo tumor xenograft models in athymic mice and rats, KRN633 inhibits the growth of tumors originating from a variety of tissues, including the prostate, lung, and colon. Additionally, KRN633 causes some well-established tumors to shrink as well as those that had grown back after treatment was stopped. KRN633 was well tolerated and had no appreciable effects on the animals' overall health or body weight. KRN633 may be helpful in treating diseases that depend on pathologic angiogenesis, such as solid tumors.
| Targets |
VEGFR1 (IC50 = 170 nM); VEGFR2 (IC50 = 160 nM); VEGFR3 (IC50 = 125 nM)
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| ln Vitro |
KRN 633 is a novel quinazoline urea derivative that has IC50 values of 170 nM, 160 nM, and 125 nM, respectively, strongly inhibiting the VEGFR1, VEGFR2, and VEGFR3 receptors. With regard to non-RTKs, such as c-Kit, breast tumor kinase, PDGF receptor (PDGFRα and β), and tunica interna endothelial cell kinase tyrosine kinases (IC50 = 965, 9850, 4330, 9200, and 9900 nM, respectively), it exhibits less inhibitory activity. With an IC50 of 1.16 nM, KRN 633 potently suppresses the ligand-induced VEGF-induced phosphorylation of VEGFR2 in HUVECs. With IC50 values of 3.51 nM and 6.08 nM for ERK1 and ERK2, respectively, KRN 633 also inhibits the phosphorylation of the MAP kinases in endothelial cells that is dependent on VEGF but not bFGF. It has also been demonstrated that KRN633 inhibits HUVECs' VEGF-driven proliferation with an IC50 of 14.9 nM, but it only marginally inhibits FGF-driven proliferation at 3 μM.[1] By inhibiting the Akt and ERK phosphorylation signaling pathways, KRN 633 inhibits the hypoxia-induced transcriptional activation of HIF-1α in a concentration-dependent manner with an IC50 of 3.79 μM.[2]
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| ln Vivo |
KRN633 has good antitumor activity in vivo because it inhibits tumor vessel formation and vascular permeability, despite not being cytotoxic to different cancer cells in vitro. When KRN633 is administered once daily at a dose of 100 mg/kg/d, it significantly inhibits the growth of tumors in A549, LC-6-LCK, HT29, Ls174T, LNCap, and Du145 cells. When administered twice daily at a dose of 100 mg/kg, however, HT29 tumors experience growth inhibition of approximately 90%.[1] When KRN 633 (300 mg/kg, p.o.) is administered to mid-pregnancy mice, the placenta and fetal organs' vascularization is reduced, which lowers the blood supply to the fetal tissues and raises the possibility of inducing intrauterine growth restriction (IUGR).[3]
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| Enzyme Assay |
To find the IC50 values against various recombinant VEGF receptors, cell-free kinase assays are performed. KRN633 is examined at concentrations ranging from 0.3 nM to 10 μM. Every assay is conducted in four duplicates using one microgram of ATP.
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| Cell Assay |
The media that contains 10% FBS and antibiotics is used to plate cancer cells at densities that are known to allow for exponential growth during the assay period. After incubating the cells for 24 hours, they are treated with KRN633 (0.01 to 10 μM) or with just the vehicle (0.1% DMSO in medium), and they are left to grow for an additional 96 hours. WST-1 reagent is used to measure the viability of cells.
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| Animal Protocol |
Rats: Human tumor xenografts are implanted in the hind flank of BALB/cA and Jcl-nu athymic rats. When the tumors reach the average size indicated (162 to 657 mm3), rats are randomized into groups of five and treated with KRN-633 or vehicle once (qd) or twice (bid) per day at the indicated dosages. On the 14th day following the last treatment, the percentage of inhibition of tumor growth is calculated in comparison to the vehicle-treated group[1].
Mice: The mice are divided into five-group randomization once the tumors reach the average sizes of 500 to 667 mm3 or 103 to 260 mm3. Following that, they receive treatment with KRN-633 or a vehicle once (qd) or twice (bid) daily at doses ranging from 10 to 100 mg/kg. The day following the final treatment, the percentage of tumor growth inhibition (TGI) relative to the vehicle-treated group is computed[1]. |
| References |
| Molecular Formula |
C20H21CLN4O4
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| Molecular Weight |
416.86
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| Exact Mass |
416.13
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| Elemental Analysis |
C, 57.62; H, 5.08; Cl, 8.50; N, 13.44; O, 15.35
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| CAS # |
286370-15-8
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| Related CAS # |
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| Appearance |
Solid powder
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| SMILES |
CCCNC(=O)NC1=C(C=C(C=C1)OC2=NC=NC3=CC(=C(C=C32)OC)OC)Cl
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| InChi Key |
VPBYZLCHOKSGRX-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C20H21ClN4O4/c1-4-7-22-20(26)25-15-6-5-12(8-14(15)21)29-19-13-9-17(27-2)18(28-3)10-16(13)23-11-24-19/h5-6,8-11H,4,7H2,1-3H3,(H2,22,25,26)
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| Chemical Name |
1-[2-chloro-4-(6,7-dimethoxyquinazolin-4-yl)oxyphenyl]-3-propylurea
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| Synonyms |
KRN633; KRN-633; KRN 633
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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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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
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| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.3989 mL | 11.9944 mL | 23.9889 mL | |
| 5 mM | 0.4798 mL | 2.3989 mL | 4.7978 mL | |
| 10 mM | 0.2399 mL | 1.1994 mL | 2.3989 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.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution 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 stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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