DW10075, a novel selective and small-molecule inhibitor of VEGFR, exhibits antitumor activities both in vitro and in vivo

Li, Mengyuan; Lv, Yongcong; Tong, Linjiang; Peng, Ting; Qu, Rong; Zhang, Tao; Sun, Yiming; Chen, Yi; Wei, Lixin; Geng, Meiyu; Duan, Wenhu; Xie, Hua; Ding, Jian

doi:10.1038/aps.2015.117

Cited by 17 publications

(12 citation statements)

References 30 publications

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“…Slides (0.5 cm Â 0.5 cm) were pretreatment with aspirin (1, 2, and 4 mmol/L) or suramin (1 and 10 mmol/L) by dropping 1 mL solution on one slide. At the next day, the slides were dried up and placed on areas between preexisting vessels, and the embryos were further incubated for 48 hours (39). The neighboring neo-vascular zones were photographed with a stereomicroscope (MS5; Leica).…”

Section: Chick Chorioallantoic Membrane Assaymentioning

confidence: 99%

Aspirin Inhibits Cancer Metastasis and Angiogenesis via Targeting Heparanase

Dai

Yan

et al. 2017

Clinical Cancer Research

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104

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Purpose: Recent epidemiological and clinical studies have suggested the benefit of aspirin for patients with cancer, which inspired increasing efforts to demonstrate the anticancer ability of aspirin and reveal the molecular mechanisms behind. Nevertheless, the anticancer activity and related mechanisms of aspirin remain largely unknown. This study aimed to confirm this observation, and more importantly, to investigate the potential target contributed to the anticancer of aspirin.Experimental Design: A homogeneous time-resolved fluorescence (HTRF) assay was used to examine the impact of aspirin on heparanase. Streptavidin pull-down, surface plasmon resonance (SPR) assay, and molecular docking were performed to identify heparanase as an aspirin-binding protein. Transwell, rat aortic rings, and chicken chorioallantoic membrane model were used to evaluate the antimetastasis and anti-angiogenesis effects of aspirin, and these phenotypes were tested in a B16F10 metastatic model, MDA-MB-231 metastatic model, and MDA-MB-435 xenograft model.Results: This study identified heparanase, an oncogenic extracellular matrix enzyme involved in cancer metastasis and angiogenesis, as a potential target of aspirin. We had discovered that aspirin directly binds to Glu225 region of heparanase and inhibits the enzymatic activity. Aspirin impeded tumor metastasis, angiogenesis, and growth in heparanase-dependent manner.Conclusions: In summary, this study has illustrated heparanase as a target of aspirin for the first time. It provides insights for a better understanding of the mechanisms of aspirin in anticancer effects, and offers a direction for the development of smallmolecule inhibitors of heparanase.

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Section: Chick Chorioallantoic Membrane Assaymentioning

confidence: 99%

Aspirin Inhibits Cancer Metastasis and Angiogenesis via Targeting Heparanase

Dai

Yan

et al. 2017

Clinical Cancer Research

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104

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“…Cytotoxicity test. HUVECs were used to evaluate the toxicity of NT-a9 (28). A total of 1 ϫ 10 5 cells/ml of HUVECs in DMEM containing 10% fetal bovine serum (FBS) was seeded in 96-well tissue culture plates and incubated for 3 h for adhesion.…”

Section: Methodsmentioning

confidence: 99%

New Triazole NT-a9 Has Potent Antifungal Efficacy against Cryptococcus neoformans In Vitro and In Vivo

et al. 2020

Antimicrob Agents Chemother

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In the past decades, the incidence of cryptococcosis has increased dramatically, which poses a new threat to human health. However, only a few drugs are available for the treatment of cryptococcosis. Here, we described a leading compound, NT-a9, an analogue of isavuconazole, that showed strong antifungal activities in vitro and in vivo. NT-a9 showed a wide range of activities against several pathogenic fungi in vitro, including Cryptococcus neoformans, Cryptococcus gattii, Candida albicans, Candida krusei, Candida tropicalis, Candida glabrata, and Candida parapsilosis, with MICs ranging from 0.002 to 1 μg/ml. In particular, NT-a9 exhibited excellent efficacy against C. neoformans, with a MIC as low as 0.002 μg/ml. NT-a9 treatment resulted in changes in the sterol contents in C. neoformans, similarly to fluconazole. In addition, NT-a9 possessed relatively low cytotoxicity and a high selectivity index. The in vivo efficacy of NT-a9 was assessed using a murine disseminated-cryptococcosis model. Mice were infected intravenously with 1.8 × 106 CFU of C. neoformans strain H99. In the survival study, NT-a9 significantly prolonged the survival times of mice compared with the survival times of the control group or the isavuconazole-, fluconazole-, or amphotericin B-treated groups. Of note, 4 and 8 mg/kg of body weight of NT-a9 rescued all the mice, with a survival rate of 100%. In the fungal-burden study, NT-a9 also significantly reduced the fungal burdens in brains and lungs, while fluconazole and amphotericin B only reduced the fungal burden in lungs. Taken together, these data suggested that NT-a9 is a promising antifungal candidate for the treatment of cryptococcosis infection.

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“…In vitro cellular antiproliferation activities of the designed compounds against H1975 and A431 cell lines were examined by using the well-established sulforhodamine B (SRB) colorimetric assay 28 . The detailed experiment was performed according to the published literature 21 .…”

Section: Methodsmentioning

confidence: 99%

Structure-Guided Design of C4-alkyl-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-ones as Potent and Mutant-Selective Epidermal Growth Factor Receptor (EGFR) L858R/T790M Inhibitors

Hao

Lyu

et al. 2017

Sci Rep

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Epidermal growth factor receptor (EGFR) T790M acquired drug-resistance mutation has become a major clinical challenge for the therapy of non-small cell lung cancer. Here, we applied a structure-guided approach on the basis of the previous reported EGFR inhibitor (compound 9), and designed a series of C4-alkyl-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-one derivatives as novel mutant-selective EGFR inhibitors. Finally, the most representative compound 20a was identified, which showed high selectivity at both enzymatic and cellular levels against EGFR L858R/T790M (H1975 cell lines) over EGFR WT (A431 cell lines). The representative compound 20a also showed promising antitumor efficiency in the in vivo antitumor efficacy study of H1975 xenograft mouse model driven by EGFR L858R/T790M . These results provide a new scaffold for the treatment of dual-mutant-driven non-small cell lung cancer.The epidermal growth factor receptor (EGFR) is a member of ErbB (HER) receptor tyrosine kinases (RTKs) family, which plays essential roles in regulation of numerous normal physiological processes, such as cell proliferation, differentiation, metabolism and apoptosis 1, 2 . Conversely, overexpression and abnormal activation of EGFR is associated with varieties of human epithelial malignancies, especially non-small cell lung cancer (NSCLC). Thus, targeting EGFR has provided an effective anticancer strategy, and EGFR has become a well-established critical target for the treatment of NSCLC 3-5 . Whereafter, activating mutations within the EGFR catalytic domain have been successively discovered, of which, the exon 21 single point substitution mutation (L858R) and the exon 19 deletion (del E746-A750) are the two most prevalent activating mutations. Detection of EGFR activating mutations provides a useful marker for predicting the potential of first generation EGFR inhibitors 6-8 . Thus, compounds 1 (gefitinib) and 2 (erlotinib), two of the first-generation EGFR-targeted small molecule inhibitors (Fig. 1) have been used in clinic for the treatment of advanced NSCLC patients harboring these specific activating mutations. The two agents demonstrated remarkable therapeutic responses for these NSCLC patients, however, acquired drug-resistance often emerged after treatment of 10-14 months, which has become a major clinical challenge for the therapy of NSCLC 9-11 . The emergence of point mutations in the EGFR kinase domain is also closely related to acquired resistances, among which, the gatekeeper T790M secondary mutation (threonine790 → methionine790 mutation) is the primary mechanism of the acquired resistances, as it is the most common mutation and accounts for approximately 60% of all clinically observed acquired mutants 12 .

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DW10075, a novel selective and small-molecule inhibitor of VEGFR, exhibits antitumor activities both in vitro and in vivo

Cited by 17 publications

References 30 publications

Aspirin Inhibits Cancer Metastasis and Angiogenesis via Targeting Heparanase

Aspirin Inhibits Cancer Metastasis and Angiogenesis via Targeting Heparanase

New Triazole NT-a9 Has Potent Antifungal Efficacy against Cryptococcus neoformans In Vitro and In Vivo

Structure-Guided Design of C4-alkyl-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-ones as Potent and Mutant-Selective Epidermal Growth Factor Receptor (EGFR) L858R/T790M Inhibitors

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