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KRN 633 Chemical Structure
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Biological Activity
| Information | KRN 633 is an ATP-competitive VEGFR kinase inhibitor of VEGFR-1, VEGFR-2 and VEGFR-3, with IC50 of 170 nM, 160 nM and 125 nM, respectively. | |||||
|---|---|---|---|---|---|---|
| Targets | VEGFR-1 | VEGFR-2 | VEGFR-3 | |||
| IC50 | 170 nM | 160 nM | 125 nM [1] | |||
| In vitro | KRN 633, a novel quinazoline urea derivative, strongly inhibits VEGFR-1, VEGFR-2 and VEGFR-3 with IC50 values of 170 nM, 160 nM and 125 nM, respectively, which has less inhibitory activity towards non-RTKs, such as PDGF receptor (PDGFR)-α and -β, c-Kit, breast tumor kinase, and tunica interna endothelial cell kinase tyrosine kinases. KRN 633 potently inhibits the ligand VEGF induced phosphorylation of VEGFR-2 in HUVECs with an IC50 of 1.16 nM. KRN 633 inhibits VEGF-dependent, but not bFGF-dependent, phosphorylation of the MAP kinases in endothelial cells, with IC50 values of 3.51 nM and 6.08 nM for ERK1 and ERK2, respectively. KRN633 inhibits the VEGF-driven proliferation of HUVECs with an IC50 of 14.9 nM, and only weakly suppresses FGF-driven proliferation at 3 μM. [1] KRN 633 inhibits the hypoxia-induced transcriptional activation of HIF-1α in a concentration-dependent manner with an IC50 of 3.79 μM, through the inhibition of both Akt and ERK phosphorylation signaling pathways. [2] | |||||
| In vivo | Although not cytotoxic to various cancer cells in vitro, KRN633 exhibits excellent antitumor activity in vivo due to its inhibitory effects on tumor vessel formation and vascular permeability. Once-daily administration of KRN633 at 100 mg/kg/d produces significant tumor growth inhibition in A549, LC-6-LCK, HT29, Ls174T, LNCap and Du145 cells, and twice-daily administration of KRN633 at 100 mg/kg induces ~90% growth inhibition of HT29 tumors. [1] Treatment with KRN 633 (300 mg/kg, p.o.) of mid-pregnancy mice reduces the blood supply to fetal tissues due to the diminished vascularization in both placenta and fetal organs and consequently increases the risk of induction of intrauterine growth restriction (IUGR). [3] | |||||
| Clinical Trials | ||||||
| Features | ||||||
Protocol
Kinase Assay: [1]
| Cell-Free Kinase Assays | Cell-free kinase assays are done to obtain IC50 values against a variety of recombinant VEGF receptor. KRN633 is tested from 0.3 nM to 10 μM. All assays are done in quadruplicate with 1 μM ATP. |
|---|
Cell Assay: [1]
| Cell lines: | A549, Ls174T, DU145, HT29, LNCap and PC-3 cell lines |
|---|---|
| Concentrations: | Dissolved in DMSO, final concentrations 0.01 to 10 μM |
| Incubation Time: | 96 hours |
| Method: | Cancer cells are plated in media with 10% FBS and antibiotics, at densities known to permit exponential growth over the assay period. The cells are cultured for 24 hours before adding KRN633 (0.01 to 10 μM) or vehicle (0.1% DMSO in medium) and then grown for a further 96 hours. Cell viability is measured using WST-1 reagent. |
Animal Study:[1]
Chemical Information
| Molecular Weight (WM): | 416.86 |
|---|---|
| Formula: | C20H21ClN4O4 |
| CAS No.: | 286370-15-8 |
| Synonyms: |
N/A
|
| Dissolve in (25°C): | DMSO ≥9mg/mL |
| Water <1mg/mL | |
| Ethanol <1mg/mL | |
| Storage: | 2 years-20°CPowder |
| 1 week-4°Cin DMSO | |
| 1 month-80°in DMSO |
Quality Control & MSDS
Research Area
Notes:
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