Novel VEGFR-2 kinase inhibitors identified by the back-to-front approach

被引：62
|
作者：
Sanphanya, Kingkan [1 ]
Wattanapitayakul, Suvara K. [2 ]
Phowichit, Suwadee [2 ]
Fokin, Valery V. [3 ]
Vajragupta, Opa [1 ]
机构：
[1] Mahidol Univ, Fac Pharm, Excellent Ctr Innovat Drug Design & Discovery, Bangkok 10400, Thailand
[2] Srinakharinwirot Univ, Fac Med, Dept Pharmacol, Bangkok 10110, Thailand
[3] Scripps Res Inst, Dept Chem, La Jolla, CA 92037 USA
来源：
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2013年 / 23卷 / 10期
关键词：
VEGFR-2; KDR; inhibitor; Molecular modeling; Antiangiogenesis; 1,4-Disubstituted 1,2,3-triazoles; CuAAC reaction; RECEPTOR TYROSINE KINASES; ENDOTHELIAL GROWTH-FACTOR; POTENT; ANGIOGENESIS; DISCOVERY; DESIGN; STRATEGY; TARGETS; CANCER; SERIES;
D O I：
10.1016/j.bmcl.2013.03.042
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
We report a novel VEGFR-2 inhibitor, developed by the back-to-front approach. Docking experiments indicated that the 3-chloromethylphenylurea motif of the lead compound occupied the back pocket of VEGFR-2 kinase. An attempt was made to enhance the binding affinity of 1 by expanding the structure to access the front pocket using a triazole linker. A library of 1,4-(disubstituted)-1H-1,2,3-triazoles were screened in silico, and one compound (VH02) was identified with an IC50 against VEGFR-2 of 0.56 mu M. VH02 showed antiangiogenic effects, inhibiting tube formation in HUVEC cells (EA.hy926) at 0.3 mu M, 13 times lower than its cytotoxic dose. These enzymatic and cellular activities suggest that VH02 has potential as a lead for further optimization. (C) 2013 Elsevier Ltd. All rights reserved.
引用
收藏
页码：2962 / 2967
页数：6
相关论文
共 50 条
  • [1] Exploration for novel inhibitors showing back-to-front approach against VEGFR-2 kinase domain (4AG8) employing molecular docking mechanism and molecular dynamics simulations
    Shailima Rampogu
    Ayoung Baek
    Amir Zeb
    Keun Woo Lee
    [J]. BMC Cancer, 18
  • [2] Exploration for novel inhibitors showing back-to-front approach against VEGFR-2 kinase domain (4AG8) employing molecular docking mechanism and molecular dynamics simulations
    Rampogu, Shailima
    Baek, Ayoung
    Zeb, Amir
    Lee, Keun Woo
    [J]. BMC CANCER, 2018, 18
  • [3] Correction to: Exploration for novel inhibitors showing back-to-front approach against VEGFR-2 kinase domain (4AG8) employing molecular docking mechanism and molecular dynamics simulations
    Shailima Rampogu
    Ayoung Baek
    Amir Zeb
    Keun Woo Lee
    [J]. BMC Cancer, 19
  • [4] Novel VEGFR-2 kinase inhibitors for the treatment of cancer
    Boyer, SJ
    Burke, JM
    Brennan, CR
    Brini, W
    Collibee, W
    Dixon, JA
    Dumas, J
    Ehrgott, F
    Hatoum-Mokdad, H
    Hong, ZQ
    Kluender, HC
    Lee, W
    Ma, X
    Reeves, R
    Sibley, RN
    Turner, T
    Wong, W
    Zhang, YL
    Brink, C
    Carter, C
    Chang, Y
    Chien, DS
    Cortes, C
    Elting, J
    Jones, RM
    McHugh, M
    Natrillo, A
    Polony, B
    Vincent, P
    Wilkie, D
    Webb, D
    Zhu, GC
    [J]. ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2005, 230 : U2505 - U2505
  • [5] Exploration for novel inhibitors showing back-to-front approach against VEGFR-2 kinase domain (4AG8) employing molecular docking mechanism and molecular dynamics simulations (vol 18, 264, 2018)
    Rampogu, Shailima
    Baek, Ayoung
    Zeb, Amir
    Lee, Keun Woo
    [J]. BMC CANCER, 2019, 19 (01)
  • [6] Photoactivatable Caged Prodrugs of VEGFR-2 Kinase Inhibitors
    Pinchuk, Boris
    Horbert, Rebecca
    Doebber, Alexander
    Kuhl, Lydia
    Peifer, Christian
    [J]. MOLECULES, 2016, 21 (05):
  • [7] Development of thienopyridines as VEGFR-2 kinase inhibitors.
    Munchhof, MJ
    Adams, MA
    Atherton, JA
    Beebe, JS
    Casavant, JC
    Cooper, BC
    Doty, JD
    Emerson, EE
    Foster, BF
    Gant, TG
    Garshasb, SG
    Goodwin, PG
    Harriman, SH
    Higdon, CH
    Hillerman, SH
    Interi, CI
    Jani, JJ
    Knauth, LK
    Marx, MM
    Natarajan, VN
    Noe, MN
    Rossi, AR
    Savage, DS
    Shaeffer, TS
    Smolarek, TS
    Snow, SS
    Sobolov, SS
    Soderstrom, ES
    Sun, JS
    Turncliff, RT
    [J]. ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2003, 225 : U197 - U197
  • [8] An Integrated Virtual Screening Approach for VEGFR-2 Inhibitors
    Zhang, Yanmin
    Yang, Shangyan
    Jiao, Yu
    Liu, Haichun
    Yuan, Haoliang
    Lu, Shuai
    Ran, Ting
    Yao, Sihui
    Ke, Zhipeng
    Xu, Jinxing
    Xiong, Xiao
    Chen, Yadong
    Lu, Tao
    [J]. JOURNAL OF CHEMICAL INFORMATION AND MODELING, 2013, 53 (12) : 3163 - 3177
  • [9] Discovery of novel Benzimidazoles as potent inhibitors of TIE-2 and VEGFR-2 tyrosine kinase receptors
    Hasegawa, Masaichi
    Nishigaki, Naohiko
    Washio, Yoshiaki
    Kano, Kazuya
    Harris, Philip A.
    Sato, Hideyuki
    Mori, Ichiro
    West, Rob I.
    Shibahara, Megumi
    Toyoda, Hiroko
    Wang, Liping
    Nolte, Robert T.
    Veal, James M.
    Cheung, Mui
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 2007, 50 (18) : 4453 - 4470
  • [10] Efficient Synthesis and Biological Activity of Novel Indole Derivatives as VEGFR-2 Tyrosine Kinase Inhibitors
    C. Zhang
    D. Xu
    J. Wang
    C. Kang
    [J]. Russian Journal of General Chemistry, 2017, 87 : 3006 - 3016
12345