Taking Quinazoline as a General Support‐Nog to Design Potent and Selective Kinase Inhibitors: Application to FMS‐like Tyrosine Kinase 3

Li, Weiwei; Chen, Jin-Juan; Zheng, Renlin; Zhang, Wenqin; Cao, Zhixing; Yang, Lingling; Qing, Xiao-Yu; Zhou, Liangxue; Yang, Li; Yu, Luo-Ding; Chen, Lijuan; Wei, Yuquan; Yang, Shengyong

doi:10.1002/cmdc.200900537

Cited by 17 publications

(12 citation statements)

References 20 publications

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“…The authors used quinazoline as the seed fragment, because three of the nine clinically approved kinase inhibitor drugs are 4-anilinoquinazoline derivatives (Li et al, 2010a). These inhibitors bind the active site of their respective targets such that the quinazoline ring is located at the front of ATP binding pocket.…”

Section: Automated De Novo Design Of Ligandsmentioning

confidence: 99%

Computational Methods in Drug Discovery

et al. 2013

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Section: Automated De Novo Design Of Ligandsmentioning

confidence: 99%

Computational Methods in Drug Discovery

et al. 2013

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“…In an effort to discover more potent VEGFR2 inhibitors, we adopted a restricted de novo design strategy for VEGFR2 inhibitors; a detailed description about this strategy can be found in our previous study (17). By using this strategy, we designed a series of inhibitors derived from quinazoline.…”

Section: Introductionmentioning

confidence: 99%

SKLB1002, a Novel Potent Inhibitor of VEGF Receptor 2 Signaling, Inhibits Angiogenesis and Tumor Growth In Vivo

Zhang

Cao

Tian

et al. 2011

Clinical Cancer Research

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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.

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“…cMc-na has been widely used due to its high viscosity, non-toxicity and non-allergenicity (16). in addition, a previous study reported that cMc-na can be used as a drug solvent to treat dry eye (17). Mouse eyes were injured through incubation with 1 mol/l naoH to induce conV.…”

Section: Discussionmentioning

confidence: 99%

“…SKlB1002, derived from quinazoline, is a small molecule that displays potent and specific inhibition of VEGFR2 tyrosine kinase activity. it can inhibit VeGF-induced phosphorylation of VeGFr2 kinase and the downstream protein kinases (16,17). a previous study has demonstrated that SKlB1002 inhibits angiogenesis and may be a potential drug candidate for anti-cancer therapy (18).…”

Section: Introductionmentioning

confidence: 98%

SKLB1002, a potent inhibitor of VEGF receptor 2 signaling, inhibits endothelial angiogenic function in�vitro and ocular angiogenesis in�vivo

et al. 2020

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ocular angiogenesis is a major cause of severe vision loss, which can affect several parts of the eye, including the retina, choroid and cornea. Vascular endothelial growth factor receptor 2 (VeGFr2) inhibitors have demonstrated great potential for treating ocular angiogenesis and SKlB1002 is a potent inhibitor of VeGF receptor 2 signaling. The present study investigated the effects of SKlB1002 administration on ocular angiogenesis. SKlB1002 administration did not show obvious cytotoxicity and tissue toxicity at the tested concentrations. in an alkali-burn corneal model, SKlB1002 administration significantly decreased the mean length and number of new corneal blood vessels. SKlB1002 administration significantly reduced endothelial cell proliferation, migration and tube formation in vitro. Mechanistically, SKlB1002 inhibited endothelial angiogenic functions by blocking the phosphorylation of erK1/2, JnK and p38. Thus, selective inhibition of VeGFr-2 through SKlB1002 administration is a promising therapy for ocular angiogenesis.

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Taking Quinazoline as a General Support‐Nog to Design Potent and Selective Kinase Inhibitors: Application to FMS‐like Tyrosine Kinase 3

Cited by 17 publications

References 20 publications

Computational Methods in Drug Discovery

Computational Methods in Drug Discovery

SKLB1002, a Novel Potent Inhibitor of VEGF Receptor 2 Signaling, Inhibits Angiogenesis and Tumor Growth In Vivo

SKLB1002, a potent inhibitor of VEGF receptor 2 signaling, inhibits endothelial angiogenic function in�vitro and ocular angiogenesis in�vivo

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