Novel Potent Orally Active Multitargeted Receptor Tyrosine Kinase Inhibitors: Synthesis, Structure−Activity Relationships, and Antitumor Activities of 2-Indolinone Derivatives

Cho, Tang Peng; Dong, Su Yi; Feng, Jiaxuan; Hong, Fu Jian; Liang, Yang; Lu, Xiao; Hua, Peng Jiang; Li, Li Ya; Zhang, Lei; Hu, Bing; Zhou, Ying; Qiong, Li Fang; Bei, Fu Bei; Guang, Lou Li; Shen, Gong Ai; Hong, She Gao; Hong, Sun Wei; Tai, Mong Xian

doi:10.1021/jm101036c

Cited by 46 publications

(16 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…6G) [73] and VEGFR2 signaling (Fig. 4–6) in agreement with EC sprouting literature[51–53,74,75] and consistent with the increased iPSC-EC sprouting we previously observed upon VEGF sequestering in the iSM[76]. Importantly, the influence of VEGFR2 inhibition on engineered sprouting behavior here was dependent on the concentration of CRGDS (Fig.…”

Section: Discussionsupporting

confidence: 90%

Human iPSC-derived endothelial cell sprouting assay in synthetic hydrogel arrays

2016

View full text Add to dashboard Cite

Activation of vascular endothelial cells (ECs) by growth factors initiates a cascade of events during angiogenesis in vivo consisting of EC tip cell selection, sprout formation, EC stalk cell proliferation, and ultimately vascular stabilization by support cells. Although EC functional assays can recapitulate one or more aspects of angiogenesis in vitro, they are often limited by undefined substrates and lack of dependence on key angiogenic signaling axes. Here, we designed and characterized a chemically-defined model of endothelial sprouting behavior in vitro using human induced pluripotent stem cell-derived endothelial cells (iPSC-ECs). We rapidly encapsulated iPSC-ECs at high density in poly(ethylene glycol) (PEG) hydrogel spheres using thiol-ene chemistry and subsequently encapsulated cell-dense hydrogel spheres in a cell-free hydrogel layer. The hydrogel sprouting array supported pro-angiogenic phenotype of iPSC-ECs and supported growth factor-dependent proliferation and sprouting behavior. iPSC-ECs in the sprouting model responded appropriately to several reference pharmacological angiogenesis inhibitors of vascular endothelial growth factor, NF-κB, matrix metalloproteinase-2/9, protein kinase activity, and β-tubulin, which confirms their functional role in endothelial sprouting. A blinded screen of 38 putative vascular disrupting compounds (pVDCs) from the US Environmental Protection Agency’s ToxCast library identified six compounds that inhibited iPSC-EC sprouting and five compounds that were overtly cytotoxic to iPSC-ECs at a single concentration. The chemically-defined iPSC-EC sprouting model (iSM) is thus amenable to enhanced-throughput screening of small molecular libraries for effects on angiogenic sprouting and iPSC-EC toxicity assessment.

show abstract

Section: Discussionsupporting

confidence: 90%

Human iPSC-derived endothelial cell sprouting assay in synthetic hydrogel arrays

2016

View full text Add to dashboard Cite

show abstract

“…In recent days many effective small-molecule kinase inhibitors have been discovered. Tang et al [46] developed a novel series of pyrrolo-fused-heterocycle-2-indolinone analogues (18 Fig. (3)) as PDGFR, VEGFR and c-Kit inhibitors.…”

Section: Growth Factors Inhibitorsmentioning

confidence: 99%

Indolinones as Promising Scaffold as Kinase Inhibitors: A Review

Prakash¹,

Raja

2012

MRMC

View full text Add to dashboard Cite

Kinases are probably the most important signaling enzymes, which represent about 20% of the druggable genome. Currently, more than 150 kinases are known. So, kinase inhibition therapy has become a very important area of drug research since most of our diseases are related to intra or intercellular signaling by kinases. Indole alkaloids are extensively studied for their biological activities in several pharmaceutical areas, including, for example, antitumor. Among this chemical family, indolinone displays very promising antitumor properties by inhibiting various kinase families. These small molecules have a low molecular weight and most of them bind to protein kinases competing with ATP for the ATP-binding site. This review focuses on the indolinone based drugs approved for the treatment of cancer, drugs under clinical trial and then chemical diversity of various synthetic analogues of indolinone and their metabolites as various kinase inhibitors. This review also focused on structural activity relationship (SAR), mechanisms of action and biological targets through which indolinone and its derivatives display their antitumor activity.

show abstract

“…The optimized fused-ring sizes of the products were found to be six and seven. The most potent analog was famitinib, a C(5)-F 2-piperidinone-fused (2-oxoindolin-3-ylidene) methylpyrrole [ 15 ]. Famitinib is a tyrosine kinase inhibitor agent targeting at c-Kit, VEGFR-2, PDGFR, VEGFR-3, Flt1, and Flt3.…”

Section: Introductionmentioning

confidence: 99%

Structural optimization and evaluation of novel 2-pyrrolidone-fused (2-oxoindolin-3-ylidene)methylpyrrole derivatives as potential VEGFR-2/PDGFRβ inhibitors

Yang

Lee

2017

Chemistry Central Journal

View full text Add to dashboard Cite

BackgroundTumor angiogenesis, essential for tumor growth and metastasis, is tightly regulated by VEGF/VEGFR and PDGF/PDGFR pathways, and therefore blocking those pathways is a promising therapeutic target. Compared to sunitinib, the C(5)-Br derivative of 2-pyrrolidone-fused (2-oxoindolin-3-ylidene)methylpyrrole has significantly greater in vitro activities against VEGFR-2, PDGFRβ, and tube formation.Results and discussionThe objective of this study was to perform further structural optimization, which revealed certain new products with even more potent anti-tumor activities, both cellularly and enzymatically. Of these, 15 revealed ten- and eightfold stronger potencies against VEGFR-2 and PDGFRβ than sunitinib, respectively, and showed selectivity against HCT116 with a favorable selective index (SI > 4.27). The molecular docking results displayed that the ligand–protein binding affinity to VEGFR-2 could be enhanced by introducing a hydrogen-bond-donating (HBD) substituent at C(5) of (2-oxoindolin-3-ylidene)methylpyrrole such as 14 (C(5)-OH) and 15 (C(5)-SH).ConclusionsAmong newly synthetic compounds, 7 and 13–15 exhibited significant inhibitory activities against VEGFR-2 and PDGFRβ. Of these, the experimental results suggest that 15 might be a promising anti-proliferative agent. Graphical abstractIC50 comparison of sunitinib, 14, and 15 against VEGFR-2 and PDGFRβ. Electronic supplementary materialThe online version of this article (doi:10.1186/s13065-017-0301-5) contains supplementary material, which is available to authorized users.

show abstract

Novel Potent Orally Active Multitargeted Receptor Tyrosine Kinase Inhibitors: Synthesis, Structure−Activity Relationships, and Antitumor Activities of 2-Indolinone Derivatives

Cited by 46 publications

References 22 publications

Human iPSC-derived endothelial cell sprouting assay in synthetic hydrogel arrays

Human iPSC-derived endothelial cell sprouting assay in synthetic hydrogel arrays

Indolinones as Promising Scaffold as Kinase Inhibitors: A Review

Structural optimization and evaluation of novel 2-pyrrolidone-fused (2-oxoindolin-3-ylidene)methylpyrrole derivatives as potential VEGFR-2/PDGFRβ inhibitors

Contact Info

Product

Resources

About