Exploration of N-(2-aminoethyl)piperidine-4-carboxamide as a potential scaffold for development of VEGFR-2, ERK-2 and Abl-1 multikinase inhibitor

Bioorg Med Chem. 2013 Sep 15;21(18):5694-706. doi: 10.1016/j.bmc.2013.07.026. Epub 2013 Jul 20.


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.

Keywords: Abl; ERK; Kinase inhibitors; Molecular docking; Support vector machine; VEGFR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / toxicity
  • Benzamides / toxicity
  • Binding Sites
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Hep G2 Cells
  • Humans
  • Imatinib Mesylate
  • K562 Cells
  • Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors*
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Molecular Docking Simulation
  • Niacinamide / analogs & derivatives*
  • Niacinamide / chemistry
  • Niacinamide / metabolism
  • Niacinamide / toxicity
  • Piperazines / toxicity
  • Piperidines / chemistry*
  • Piperidines / metabolism
  • Piperidines / toxicity
  • Protein Binding
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / metabolism
  • Protein Kinase Inhibitors / toxicity
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins c-abl / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-abl / metabolism
  • Pyrimidines / toxicity
  • Pyrrolidines / chemistry*
  • Pyrrolidines / metabolism
  • Pyrrolidines / toxicity
  • Structure-Activity Relationship
  • Triazoles / chemistry*
  • Triazoles / metabolism
  • Triazoles / toxicity
  • Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism


  • (S)-1-((S)-2-amino-3-(4-(1-(4-fluorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)propanoyl)pyrrolidine-2-carbonitrile hydrochloride
  • Antineoplastic Agents
  • Benzamides
  • N-(4-((2-(2-(naphthaen-1-yl)acetamido)ethyl)carbamoyl)piperidin-4-yl)-6-(trifluoromethyl)nicotinamide
  • Piperazines
  • Piperidines
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Pyrrolidines
  • Triazoles
  • Niacinamide
  • Imatinib Mesylate
  • Vascular Endothelial Growth Factor Receptor-2
  • Proto-Oncogene Proteins c-abl
  • Mitogen-Activated Protein Kinase 1