Please use this identifier to cite or link to this item: https://doi.org/10.1016/j.bmc.2013.07.026
Title: Exploration of N-(2-aminoethyl)piperidine-4-carboxamide as a potential scaffold for development of VEGFR-2, ERK-2 and Abl-1 multikinase inhibitor
Authors: Jin, F.
Gao, D.
Wu, Q.
Liu, F.
Chen, Y. 
Tan, C.
Jiang, Y.
Keywords: Abl
ERK
Kinase inhibitors
Molecular docking
Support vector machine
VEGFR
Issue Date: 15-Sep-2013
Citation: Jin, F., Gao, D., Wu, Q., Liu, F., Chen, Y., Tan, C., Jiang, Y. (2013-09-15). Exploration of N-(2-aminoethyl)piperidine-4-carboxamide as a potential scaffold for development of VEGFR-2, ERK-2 and Abl-1 multikinase inhibitor. Bioorganic and Medicinal Chemistry 21 (18) : 5694-5706. ScholarBank@NUS Repository. https://doi.org/10.1016/j.bmc.2013.07.026
Abstract: VEGFR, ERK and Abl had been respectively identified as good drug targets, and their crosstalk also had been well elaborated. Multitarget drugs were more advantageous for cancer treatment, however, no inhibitors simultaneously acting on the three proteins were developed due to their structural diversities. Herein, N-(4-((2-(2-(naphthaen-1-yl)acetamido)ethyl)carbamoyl)piperidin-4-yl)-6- (trifluoromethyl)nicotinamide (NEPT, 6a) was discovered as an active scaffold against VEGFR-2, ERK-2 and Abl-1 kinases through the combination of support vector machine, similarity searching and molecular docking. NEPT and its derivatives were synthesized by convenient routine, their in vitro anti-proliferative abilities against human liver cancer cell line HepG2 were preliminarily evaluated. A representative compound 6b showed an IC50 value of 11.3 μM and induced significant HepG2 cells apoptosis. Besides, these compounds displayed better anti-proliferative abilities against K562 cells (a cell line with typical hyperactivity of the above multikinases), for example compound 6b exhibited an IC50 value of 4.5 μM. Based on hepatotoxicity case reports of Abl inhibitors, cytotoxicity of synthetic compounds against normal liver cell lines (QSG7701 and HL7702) was studied, 6b had a similar toxic effect with positive control imatinib, and most compounds showed less than 35% inhibition activities at 100 μM. Molecular docking study disclosed interactions of 6b with VEGFR-2, ERK-2 and Abl-1 kinases, respectively. Our data suggested the biological activities of 6b may derived from collaborative effects of VEGFR-2, ERK-2 and Abl-1 inhibition. © 2013 Elsevier Ltd. All rights reserved.
Source Title: Bioorganic and Medicinal Chemistry
URI: http://scholarbank.nus.edu.sg/handle/10635/105944
ISSN: 09680896
DOI: 10.1016/j.bmc.2013.07.026
Appears in Collections:Staff Publications

Show full item record
Files in This Item:
There are no files associated with this item.

SCOPUSTM   
Citations

11
checked on Oct 16, 2018

WEB OF SCIENCETM
Citations

8
checked on Oct 8, 2018

Page view(s)

41
checked on Oct 5, 2018

Google ScholarTM

Check

Altmetric


Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.