SKLB1002

SKLB1002 is a potent inhibitor of VEGF receptor 2 with IC50 value of 32 nM [1].

VEGF receptor 2 (VEGFR2) is a major receptor for vascular endothelial growth factor (VEGF) and plays an important role in angiogenesis and VEGF-stimulated proliferation, migration, and sprouting of cultured endothelial cells [1].

SKLB1002 is a potent VEGFR2 inhibitor. In human umbilical vein endothelial cells (HUVEC), SKLB1002 significantly inhibited VEGF-induced HUVEC proliferation with IC50 value of 11.9 μM. Also, SKLB1002 inhibited HUVEC migration, invasion and tube formation in a dose-dependent way. SKLB1002 (10 μM) significantly inhibited VEGF-induced phosphorylation of VEGFR2, ERK, Src and FAK [1].

In zebrafish embryos, SKLB1002 (2.5 μM) significantly inhibited the growth of intersegmental vessels. In mice bearing SW620 or HepG2 xenografts, SKLB1002 (100 mg/kg) significantly inhibited tumor volume and inhibited tumor growth by 60%. Also, SKLB1002 reduced the microvessel density [1]. In mice with 4T1 tumor, SKLB1002 significantly reduced the tumor vessel density [2].

References:
[1].  Zhang S, Cao Z, Tian H, et al. SKLB1002, a novel potent inhibitor of VEGF receptor 2 signaling, inhibits angiogenesis and tumor growth in vivo. Clin Cancer Res, 2011, 17(13): 4439-4450.
[2].  Shen G, Li Y, Du T, et al. SKLB1002, a novel inhibitor of VEGF receptor 2 signaling, induces vascular normalization to improve systemically administered chemotherapy efficacy. Neoplasma, 2012, 59(5): 486-493.

SKLB1002, a novel inhibitor of VEGF receptor 2 signaling, induces vascular normalization to improve systemically administered chemotherapy efficacy.[Pubmed:22668017]

Neoplasma. 2012;59(5):486-93.

Vascular endothelial growth factor receptor (VEGFR) or vascular endothelial growth factor (VEGF) inhibitors have shown only modest clinical activity for most tumor types when used as single agents. However, present evidence indicates that these antiangiogenic drugs can cause transient "normalization" of the tumor vasculature, thereby improving the delivery of systemic chemotherapy. We examined temporal changes in tumor vascular function in response to the novel VEGFR2 inhibitor, SKLB1002. Established tumor-bearing animals were evaluated at serial time points for treatment-associated changes in tumor vascular architecture and function. As a result, blocking VEGF signaling by SKLB1002 produced a morphologically and functionally "normalized" vascular network. Consistent with our observations, a 2.2 fold increase in intratumoral doxorubicin levels was determined with SKLB1002 pretreatment compared with administration of doxorubicin alone. Finally, combined SKLB1002 and doxorubicin exhibited significant antitumor (49% of control size) and antimetastatic effects (12% of control metastatic nodules) in vivo. Our results showed SKLB1002 induced vascular normalization and enhanced anticancer drug delivery, which were associated with the observed synergistic effect in vivo.

Synergic antitumor effect of SKLB1002 and local hyperthermia in 4T1 and CT26.[Pubmed:23263406]

Clin Exp Med. 2014 May;14(2):203-13.

A de novo VEGFR2-inhibited compound SKLB1002 which is independently developed in our laboratory has been described for antiangiogenesis and displays a potent antitumor activity in vivo and in vitro. In the present investigation, we aim to prove that combination therapy of SKLB1002 with hyperthermia plays a synergy as an antitumor agent in solid tumor. In this study, we analyzed their synergetic inhibitory action on human umbilical vein endothelial cells (HUVEC), murine mammary cancer 4T1, murine colon carcinoma CT26 in vitro. Multiply-table tournament was performed to detect cell proliferation in vitro. 4T1 implantation and CT26 implantation in BALB/c mice were used to examine the activity of combination therapy of SKLB1002 with hyperthermia in vivo. Vascular density was determined by CD31 immunohistochemistry. TUNEL was used to measure apoptosis in tumor tissue. Metastasis assay was investigated via measurement of pulmonary metastasis nodules under the microscope. Potential toxicity of combination therapy was observed by histologic analysis of main organs stained with H&E. In vitro, the combination therapy significantly inhibited cell proliferation of HUVEC, 4T1 and CT26. In vivo, 4T1 and CT26 model experiments showed that combination therapy remarkably inhibited tumor growth and prolonged life span. When compared with controls, combination therapy reached 61 % inhibition index of tumor growth against CT26 and 51 % against 4T1. Moreover, it reduced angiogenesis and increased tumor apoptosis and necrosis. It was further found that combination therapy could efficiently prevent tumor from metastasizing to lung. Importantly, it had no toxicity to main organs including heart, liver, spleen, lung and kidney. Combination treatment has been proved to be a novel and strong strategy in clinical antitumor therapy. Our findings suggest that the combination therapy of SKLB1002 with hyperthermia has a synergistic antiangiogenesis, anticancer and promotion of apoptosis efficacy compared with controls. These findings could pave a new way in clinical tumor therapy.

SKLB1002, a novel potent inhibitor of VEGF receptor 2 signaling, inhibits angiogenesis and tumor growth in vivo.[Pubmed:21622720]

Clin Cancer Res. 2011 Jul 1;17(13):4439-50.

PURPOSE: VEGF receptor 2 (VEGFR2) inhibitors, as efficient antiangiogenesis agents, have been applied in the cancer treatment. However, currently most of these anticancer drugs suffer some adverse effects. Discovery of novel VEGFR2 inhibitors as anticancer drug candidates is still needed. EXPERIMENTAL DESIGN: In this investigation, we adopted a restricted de novo design method to design VEGFR2 inhibitors. We selected the most potent compound SKLB1002 and analyzed its inhibitory effects on human umbilical vein endothelial cells (HUVEC) in vitro. Tumor xenografts in zebrafish and athymic mice were used to examine the in vivo activity of SKLB1002. RESULTS: The use of the restricted de novo design method indeed led to a new potent VEGFR2 inhibitor, SKLB1002, which could significantly inhibit HUVEC proliferation, migration, invasion, and tube formation. Western blot analysis was conducted, which indicated that SKLB1002 inhibited VEGF-induced phosphorylation of VEGFR2 kinase and the downstream protein kinases including extracellular signal-regulated kinase, focal adhesion kinase, and Src. In vivo zebrafish model experiments showed that SKLB1002 remarkably blocked the formation of intersegmental vessels in zebrafish embryos. It was further found to inhibit a new microvasculature in zebrafish embryos induced by inoculated tumor cells. Finally, compared with the solvent control, administration of 100 mg/kg/d SKLB1002 reached more than 60% inhibition against human tumor xenografts in athymic mice. The antiangiogenic effect was indicated by CD31 immunohistochemical staining and alginate-encapsulated tumor cell assay. CONCLUSIONS: Our findings suggest that SKLB1002 inhibits angiogenesis and may be a potential drug candidate in anticancer therapy.