Discovery of Potent VEGFR-2 Inhibitors based on Furopyrimidine and Thienopyrimidne Scaffolds as Cancer Targeting Agents

Aziz, M. Abdel; Serya, Rabah A. T.; Lasheen, Deena S.; Abdel-Aziz, Amal Kamal; Esmat, Ahmed; Mansour, Ahmed M.; Singab, Abdel Nasser B.; Abouzid, Khaled A. M.

doi:10.1038/srep24460

Cited by 144 publications

(104 citation statements)

References 60 publications

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“…cerebral cavernous malformation)1314 and cancer angiogenesis151617. HUVECs purchased from the Institute of Cell Biology of the Chinese Academy of Sciences (Shanghai, China) were also used in our previous in vitro studies1218.…”

Section: Resultsmentioning

confidence: 99%

HIF-1α and HIF-2α induced angiogenesis in gastrointestinal vascular malformation and reversed by thalidomide

Feng

Chen

et al. 2016

Sci Rep

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Thalidomide is used in clinical practice to treat gastrointestinal vascular malformation (GIVM), but the pathogenesis of GIVM is not clear. Hypoxia inducible factor 1 alpha (HIF-1α) and 2 alpha (HIF-2α/EPAS1) are in the same family and act as master regulators of the adaptive response to hypoxia. HIF-1α and HIF-2α are up-regulated in vascular malformations in intestinal tissues from GIVM patients, but not in adjacent normal vessels. Therefore, we investigated the role of HIF-1α and HIF-2α during angiogenesis and the mechanism of thalidomide action. In vitro experiments confirmed that vascular endothelial growth factor (VEGF) was a direct target of HIF-2α and that HIF-1α and HIF-2α regulated NOTCH1, Ang2, and DLL4, which enhanced vessel-forming of endothelial cells. Thalidomide down-regulated the expression of HIF-1α and HIF-2α and inhibited angiogenesis. In vivo zebrafish experiments suggested that HIF-2α overexpression was associated with abnormal subintestinal vascular (SIV) sprouting, which was reversed by thalidomide. This result indicated that thalidomide regulated angiogenesis via the inhibition of HIF-1α and HIF-2α expression, which further regulated downstream factors, including VEGF, NOTCH1, DLL4, and Ang2. The abnormally high expression of HIF-1α and HIF-2α may contribute to GIVM.

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Section: Resultsmentioning

confidence: 99%

HIF-1α and HIF-2α induced angiogenesis in gastrointestinal vascular malformation and reversed by thalidomide

Feng

Chen

et al. 2016

Sci Rep

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“…The binding of VEGF-A to VEGFR-2 can induce a cascade of signaling pathways, eventually causing cellular proliferation and endothelial cell survival 18,19. Several studies have confirmed that blocking VEGFR-2 was a promising therapy for inhibiting angiogenesis 20,21.…”

Section: Discussionmentioning

confidence: 99%

Salvage treatment with apatinib for advanced non-small-cell lung cancer

Song¹,

Yu²,

Lou³

et al. 2017

OTT

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ObjectiveNo definitive chemotherapeutic regimen has been established in patients with non-small-cell lung cancer (NSCLC) who failed second- or third-line treatment. The aim of this study was to evaluate apatinib, a VEGFR-2 inhibitor, in advanced NSCLC as salvage treatment.MethodsWe evaluated the efficacy and toxicity of apatinib in patients with previously treated advanced NSCLC from 2014 to 2015 in Zhejiang Cancer Hospital. Survival analysis was performed by the Kaplan–Meier method.ResultsForty-two patients were included in the present study. Four patients achieved partial response, and 22 achieved stable disease, representing a response rate of 9.5% and a disease control rate of 61.9%. Median progression-free survival and overall survival were 4.2 and 6.0 months, respectively. The toxicities associated with apatinib were generally acceptable with a total grade 3/4 toxicity of 50%.ConclusionApatinib appears to have some activity against advanced NSCLC when utilized as salvage treatment.

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“…The target compounds 29a–f were evaluated for their ability to in vitro inhibit VEGFR‐2 kinase enzyme. Several compounds demonstrated highly potent dose‐related VEGFR‐2 inhibition with IC 50 values in nanomolar range (Table ) .…”

Section: Tyrosine Kinasesmentioning

confidence: 99%

Medicinal Attributes of Thienopyrimidine Based Scaffold Targeting Tyrosine Kinases and Their Potential Anticancer Activities

Ghith

Ismail

Youssef

et al. 2017

Archiv der Pharmazie

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Thienopyrimidines (TP), comprising a thiophene ring fused with pyrimidine, are famous bioisosteres to purines, an essential part of the human metabolome. This scaffold has become an interesting structural element in the development of pharmaceutical compounds, due to their wide spectrum applications as cytotoxic agents against different types of human cancer cell lines, cGMP phosphodiesterase inhibitors, and anti-viral, anti-inflammatory, and anti-microbial agents. The structural similarity of this scaffold with adenine made it an excellent moiety to be used in the design of kinase inhibitors. This review focuses on the chemistry of thienopyrimidine derivatives, their potential activities against various kinases, and their structure-activity relationship studies.

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Discovery of Potent VEGFR-2 Inhibitors based on Furopyrimidine and Thienopyrimidne Scaffolds as Cancer Targeting Agents

Cited by 144 publications

References 60 publications

HIF-1α and HIF-2α induced angiogenesis in gastrointestinal vascular malformation and reversed by thalidomide

HIF-1α and HIF-2α induced angiogenesis in gastrointestinal vascular malformation and reversed by thalidomide

Salvage treatment with apatinib for advanced non-small-cell lung cancer

Medicinal Attributes of Thienopyrimidine Based Scaffold Targeting Tyrosine Kinases and Their Potential Anticancer Activities

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