Discovery of novel VEGFR-2 inhibitors. Part 5: Exploration of diverse hinge-binding fragments via core-refining approach

European Journal of Medicinal Chemistry
Yuanyuan ShanJie Zhang

Abstract

Pathological angiogenesis plays a critical role in numerous diseases including malignancy. VEGFR-2 is the central regulators in angiogenesis and has become a promising target for anticancer drug design. We have identified a novel biphenyl-aryl urea incorporated with salicyladoxime (BPS-7) as potent VEGFR-2 inhibitor. As a continuation to our previous research, various aromatic-heterocyclic were introduced as hinge-binding fragment via a core-refining approach. Interestingly, many compounds exhibited comparable VEGFR-2 inhibition to Sorafenib. In particular, 12e and 12o displayed excellent VEGFR-2 inhibitory activity with IC₅₀ values of 0.50 nM and 0.79 nM, respectively. Several title compounds showed considerable antiproliferative activity against A549 and SMMC-7721 cells. In addition, molecular docking was performed to rationalize the efficiency of the better compounds. These results will be instructive for further inhibitor design and optimization.

References

Dec 17, 2009·Bioorganic & Medicinal Chemistry Letters·Jie ZhangLangchong He
Mar 23, 2010·European Journal of Medicinal Chemistry·Jie ZhangLangchong He
Sep 28, 2010·Nature Cell Biology·Lars JakobssonHolger Gerhardt
Apr 26, 2011·European Journal of Medicinal Chemistry·Fan ZhangPing Gong
Nov 9, 2011·Nature Medicine·Sara M Weis, David A Cheresh
Nov 21, 2013·Current Medicinal Chemistry·C WangJ Zhang
Mar 29, 2014·European Journal of Medicinal Chemistry·Chenshu LuHaihong Huang
Dec 3, 2014·European Journal of Medicinal Chemistry·Hongping GaoJie Zhang
Feb 1, 2015·Bioorganic & Medicinal Chemistry·Wen LuJie Zhang

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Citations

Jan 13, 2016·Bioorganic & Medicinal Chemistry·Yuanyuan ShanYalin Dong

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