KRN 633是一种ATP竞争性的VEGFR1/2/3抑制剂，IC50为170 nM/160 nM/125 nM，微弱抑制PDGFR-α/β和c-Kit，对细胞中FGFR-1， EGFR和c-Met的磷酸化没有抑制作用。KRN 633是新型喹唑啉尿素衍生物, 强抑制VEGFR-1, VEGFR-2 和VEGFR-3，IC50分别为170 nM,160 nM和125 nM,对非受体酪氨酸激酶, 如PDGF受体(PDGFR)-α和-β,c-Kit, 乳腺肿瘤激酶,及内膜内皮细胞激酶酪氨酸激酶的抑制效果不明显， IC50分别为965, 9,850, 4,330, 9,200, 和 9,900 nM。KRN 633 作用于HUVECs，有效抑制配体VEGF诱导的VEGFR-2磷酸化，IC50为1.16 nM。KRN 633作用于内皮细胞，抑制VEGF依赖的,但是非bFGF依赖的MAP 激酶磷酸化,作用于ERK1 和 ERK2，IC50 分别为3.51 nM和 6.08 nM。

>98%

Store at -20℃ for one year（Powder）；Store at 2-4℃ for two weeks；Store at -20℃ for six months after dissolution.

KRN-633

白色粉末

DMSO ：≥8 mg/mL

VEGFR3,VEGFR2,VEGFR1,PDGFRα,c-Kit,,

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.

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).