product name KRN 633
Description: KRN 633 is a potent, selective, and ATP-competitive inhibitor of VEGFR1/2/3 with IC50 of 170 nM/160 nM/125 nM, weakly inhibits PDGFR-α/β and c-Kit, does not block the phosphorylation of FGFR-1, EGFR or c-Met in cell. KRN633 inhibits tumor growth in several in vivo tumor xenograft models with diverse tissue origins, including lung, colon, and prostate, in athymic mice and rats.
References: Mol Cancer Ther. 2004 Dec;3(12):1639-49; Cancer Lett. 2010 Oct 1;296(1):17-26; J Pharmacol Sci. 2010;112(3):290-8.
416.86
Formula
C20H21ClN4O4
CAS No.
286370-15-8
Storage
-20℃ for 3 years in powder form
-80℃ for 2 years in solvent
Solubility (In vitro)
DMSO: 9 mg/mL (21.6 mM)
Water: <1 mg/mL
Ethanol: <1 mg/mL
Solubility (In vivo)
0.5% methylcellulose+0.2% Tween 80: 10 mg/mL
Synonyms
other peoduct :
| In Vitro |
In vitro activity: KRN 633, a novel quinazoline urea derivative, strongly inhibits VEGFR1, VEGFR2 and VEGFR3 receptors with IC50 values of 170 nM, 160 nM and 125 nM respectively. It shows lower inhibitory activity towards non-RTKs, such as PDGF receptor (PDGFRα and β, c-Kit, breast tumor kinase, and tunica interna endothelial cell kinase tyrosine kinases (IC50 = 965, 9850, 4330, 9200, and 9900 nM, respectively). KRN 633 potently inhibits ligand VEGF induced phosphorylation of VEGFR2 in HUVECs with an IC50 of 1.16 nM. KRN 633 also 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 has also been shown to inhibit the VEGF-driven proliferation of HUVECs with an IC50 of 14.9 nM, but it only suppresses FGF-driven proliferation at 3 μM weakly. KRN 633 inhibits 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. Kinase Assay: Cell-free kinase assays are done to obtain IC50 values against a variety of recombinant VEGF receptors. KRN633 is tested at concentrations varying from 0.3 nM to 10 μM. All assays are done in quadruplicate with 1 μM ATP. Cell Assay: Cancer cells (A549, Ls174T, DU145, HT29, LNCap and PC-3 cell lines) are plated in media containig 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 just the vehicle (0.1% DMSO in medium) and then grown for a further 96 hours. Cell viability is measured using WST-1 reagent. |
|---|---|
| In Vivo | Although not cytotoxic to various cancer cells in vitro, KRN633 exhibits excellent antitumor activity in vivo due to its inhibitory effect 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 while twice-daily administration of KRN633 at 100 mg/kg induces ~90% growth inhibition of HT29 tumors. Treatment of mid-pregnancy mice with KRN 633 (300 mg/kg, p.o.) reduces the blood supply to fetal tissues due to diminished vascularization in both placenta and fetal organs and consequently increases the risk of induction of intrauterine growth restriction (IUGR). |
| Animal model | Athymic mice (BALB/cA, Jcl-nu) and athymic rats (F344/N, Jcl-rnu) bearing A549, Ls174T, HT29, DU145, LNCap, PC-3 cells and LC-6-JCK respectively. |
| Formulation & Dosage | Dissolved in vehicle (0.5% methylcellulose solution); 20-100 mg/kg; oral gavage |
| References | Mol Cancer Ther. 2004 Dec;3(12):1639-49; Cancer Lett. 2010 Oct 1;296(1):17-26; J Pharmacol Sci. 2010;112(3):290-8. |
