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. Clin Cancer Res; 17(13); 4439–50. ©2011 AACR.
An optical image encryption technique based on compressive sensing using fully optical means has been proposed. An object image is first encrypted to a white-sense stationary noise pattern using a double random phase encoding (DRPE) method in a Mach-Zehnder interferometer. Then, the encrypted image is highly compressed to a signal using single-pixel compressive holographic imaging in the optical domain. At the receiving terminal, the encrypted image is reconstructed well via compressive sensing theory, and the original image can be decrypted with three reconstructed holograms and the correct keys. The numerical simulations show that the method is effective and suitable for optical image security transmission in future all-optical networks because of the ability of completely optical implementation and substantially smaller hologram data volume.
Three‐dimensional printing (3DP) of surimi requires a structural modifier to achieve a stable construct. This work investigated the effect of addition of sweet potato starch (0–10% wt/wt) on the physical properties (rheological properties, gel strength, water‐holding capacity [WHC], and microstructural characteristics) of surimi gels and the 3D printed behavior of these gels. The results showed that as the starch content increased, the viscosity of the starch–surimi mixture decreased facilitating the flow of the surimi out of the printer nozzle. The surimi gel with 8% sweet potato starch concentration showed good gel strength (2,021.70 g mm), WHC (82.39%), microstructural characteristics, and less cooking loss (1.95%). A comparison of the traditional surimi preparation method with 3DP showed that the surimi gel prepared by a 3D printed construct was softer in gel strength (1,398.65 g mm) and lower in hardness (945.17 g) although showing slightly higher cooking loss (6.76%) and lower WHC (72.66 g) than the conventional product. The results suggest that sweet potato starch can be effectively used as a structural enhancer for 3DP complex‐shaped surimi.
In this investigation, we describe the discovery of novel potent Pim-1 inhibitors by employing a proposed hierarchical multistage virtual screening (VS) approach, which is based on support vector machine-based (SVM-based VS or SB-VS), pharmacophore-based VS (PB-VS), and docking-based VS (DB-VS) methods. In this approach, the three VS methods are applied in an increasing order of complexity so that the first filter (SB-VS) is fast and simple, while successive ones (PB-VS and DB-VS) are more time-consuming but are applied only to a small subset of the entire database. Evaluation of this approach indicates that it can be used to screen a large chemical library rapidly with a high hit rate and a high enrichment factor. This approach was then applied to screen several large chemical libraries, including PubChem, Specs, and Enamine as well as an in-house database. From the final hits, 47 compounds were selected for further in vitro Pim-1 inhibitory assay, and 15 compounds show nanomolar level or low micromolar inhibition potency against Pim-1. In particular, four of them were found to have new scaffolds which have potential for the chemical development of Pim-1 inhibitors.
Antagonizing vascular endothelial growth factor receptor 2 (VEGFR2) to block angiogenesis has been applied toward cancer therapy for its role in promoting cancer growth and metastasis. However, most these clinical anticancer drugs have unexpected side effects. Development of novel VEGFR2 inhibitors with less toxicity remains an urgent need. In this study, we describe a novel, well-tolerated, and orally active VEGFR2 inhibitor, YLT192, which inhibits tumor angiogenesis and growth. YLT192 significantly inhibited kinase activity of VEGFR2 and suppressed proliferation, migration, invasion, and tube formation of human umbilical vascular endothelial cells (HUVEC) in vitro. In addition, it inhibited VEGF-induced phosphorylation of VEGFR2 and its downstream signaling regulator in HUVEC. Zebrafish embryonic models and alginate-encapsulated tumor cell assays indicated YLT192 also inhibited angiogenesis in vivo. Moreover, YLT192 could directly inhibit proliferation and induce apoptosis of cancer cells in vitro and in vivo. Oral administration of YLT192 at a dose of 100 mg/kg/day could markedly inhibited human tumor xenograft growth without causing obvious toxicities. It decreased microvessel densities (MVD) in tumor sections. It also shows good safety profiles in the studies with mice and rats. Taken together, these preclinical evaluations suggest that YLT192 inhibits angiogenesis and may be a promising anticancer drug candidate.
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