A preclinical evaluation of a novel multikinase inhibitor, SKLB-329, as a therapeutic agent against hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) is a serious life-threatening malignant disease of liver. Molecular targeted therapies are considered a promising strategy for the treatment of HCC. Sorafenib is the first, and so far the only targeted drug approved by the US Food and Drug Administration (FDA) for clinical therapy of HCC. Despite being effective in some HCC patients, some demerits of sorafenib in the treatment of HCC, such as modest survival benefits, and drug resistance, have also been reported, which highlights the unmet medical need among patients with HCC. Here, we report a novel multikinase inhibitor discovered by us, SKLB-329, which potently inhibits angiogenesis-related kinases including VEGFR1/2/3, and FGFR2, and the Src kinase. SKLB-329 significantly inhibited endothelial cell growth, migration, invasion and tube formation. It showed potent anti-angiogenic activity in a transgenic zebrafish model. Moreover, SKLB-329 could efficiently restrain the proliferation of HCC cells through down-regulation of Src-mediated FAK and Stat3 activity. In vivo, oral administration of SKLB-329 considerably suppressed the tumor growth in HCC xenograft models (HepG2 and SMMC7721) in a dose-dependent manner. In all of the in vitro and in vivo assays of this investigation, sorafenib was used as a positive control, and in most assays SKLB-329 exhibited a higher potency compared with the positive control. In addition, SKLB-329 also bears favorable pharmacokinetic properties. Collectively, the results of preclinical studies presented here demonstrate that SKLB-329 is a promising drug candidate for HCC treatment.
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Sichuan, China.
Lei
L
Zhong
Xiao-Yu
XY
Fu
Chan
C
Zou
Ling-Ling
LL
Yang
Shu
S
Zhou
Jiao
J
Yang
Yun
Y
Tang
Chuan
C
Cheng
Lin-Li
LL
Li
Rong
R
Xiang
Li-Juan
LJ
Chen
Yu-Zong
YZ
Chen
Yu-Quan
YQ
Wei
Sheng-Yong
SY
Yang
D020533:Angiogenesis Inhibitors / Q000737:chemistry; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D004353:Drug Evaluation, Preclinical; D042783:Endothelial Cells / Q000166:cytology; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D008099:Liver / Q000378:metabolism; D008113:Liver Neoplasms / Q000188:drug therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D009536:Niacinamide / Q000031:analogs & derivatives / Q000737:chemistry; D010671:Phenylurea Compounds / Q000737:chemistry / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000737:chemistry*; D011720:Pyrazoles / Q000737:chemistry / Q000627:therapeutic use*; D015398:Signal Transduction; D000077157:Sorafenib; D015027:Zebrafish
C000593421:1-(4-((1H-pyrazolo(3,4-d)pyrimidin-4-yl)oxy)-2-fluorophenyl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea; D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D009536:Niacinamide; D000077157:Sorafenib
SKLB-329; Src; anti-angiogenesis; hepatocellular carcinoma; multi-kinase inhibitor