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functional groups have different angle with Lenalidomide lead to
different activity. Structure of sulfonyl derivative is more suitable
with FGFR-4 molecules, also the molecular docking result. The
consistent of anti-tumor activity on EC9706 with that of
molecular docking, shown that the angiogenesis docking is
feasible and the FGFR-4 is the potential target for Lenalidomide
derivatives.
Table 4
Inhibitory activity of Lenalidomide derivatives on EC9706
IC50
(µg/mL)
∆G
Compd
R
7. S.K. T., Properties of Thalidomide and its Analogues Implications
for Anticancer Therapy, AAPS J, (2005) 14-19.
(kcal/mol)a
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clinical activity in Solid Tumors, Curr Oncol Rep, (2007) 120-
123.
309.5
261.8
225.2
340.3
-7.19
-7.68
-8.40
-7.05
1d
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2e
3c
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H
Lenalidomide
a: Calculated
In this paper, a series of Lenalidomide derivatives were
designed by the virtual screening of the molecular targets of anti-
tumor angiogenesis. The results show that the angiogenesis
molecular target of Lenalidomide is innitialy FGFR-4. The
Lenalidomide derivatives were designed by modification of the
amino group of Lenalidomide. The intended structures of
Lenalidomide derivatives were identified as the alkylation,
acylation and sulfonylation of Lenalidomide with a binding free
energy ∆G values between -11.11 kcal/mol and -5.37 kcal/mol,
inhibition rate constant Ki values from 0.072 µM to 115 µM. The
Lenalidomide derivatives were synthesized and verified by the
1H-NMR, 13C-NMR and LC-MS. CCK-8 was used to detect the
inhibitory activity of Lenalidomide derivatives in the esophageal
carcinoma cell line EC9706. The results indicate that the
inhibitory activity IC50 of Lenalidomide derivatives 1d, 2e and 3c
were 261.8 µg/mL, 309.5 µg/mL and 225.2 µg/mL. It shows that
the Lenalidomide derivatives have better angiogenesis inhibitory
than Lenalidomide (IC50=340.3 µg/mL).
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Verma, Mechanism of action of lenalidomide in hematological
malignancies, J Hematol Oncol, 2 (2009) 36.
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Janku, R. Zinner, S. Laday, M. Kies, A.M. Tsimberidou, Phase I
clinical trial of lenalidomide in combination with temsirolimus in
patients with advanced cancer, Invest New Drugs, 31 (2013)
1505-1513.
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Nolte, A. H. Epperly, Discovery and Evaluation of 2-Anilino-5-
aryloxazoles as a Novel Class of VEGFR2 Kinase Inhibitors, J
Med Chem, 48 (2005) 1610-1619.
16. F. Shi, S.E. Telesco, Y. Liu, R. Radhakrishnan, M.A. Lemmon,
ErbB3/HER3 intracellular domain is competent to bind ATP and
catalyze autophosphorylation, Proc Natl Acad Sci U S A, 107
(2010) 7692-7697.
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Neubert, N.S. Gray, X. Li, M. Mohammadi, DFG-out mode of
inhibition by an irreversible type-1 inhibitor capable of
overcoming gate-keeper mutations in FGF receptors, ACS Chem
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Acknowledgments
18. E. Weisberg, P.W. Manley, W. Breitenstein, J. Bruggen, S.W.
Cowan-Jacob, A. Ray, B. Huntly, D. Fabbro, G. Fendrich, E. Hall-
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Gilliland, J.D. Griffin, Characterization of AMN107, a selective
inhibitor of native and mutant Bcr-Abl, Cancer Cell, 7 (2005) 129-
141.
This study was supported by 2015 Beijing Natural Science
Foundation (No. KZ201510005007).
A Supplementary data
Supplementary data associated with this article can be found,
in the online version, at XXX Including methods of docking
synthesis and activity testing of compounds described in this
article, and data of 1H-NMR, 13C-NMR and LC-MS.
19. R. Diskin, D. Engelberg, O. Livnah, A novel lipid binding site
formed by the MAP kinase insert in p38 alpha, J Mol Biol, 375
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Gonnelli, Matrix metalloproteinase–inhibitor interaction the
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