Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 25, Issue 13, Pages 3500-3511Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2017.04.047
Keywords
p21-Activated kinase; PAK4 inhibitor; lndolin-2-one; Structure-activity relationship; Molecular docking
Funding
- National Natural Science Foundation of China [81230077]
- Program for Innovative Research Team of the Ministry of Education
- Program for Liaoning Innovative Research Team in University
Ask authors/readers for more resources
Utilizing a pharmacophore hybridization approach, a novel series of substituted indolin-2-one derivatives were designed, synthesized and evaluated for their in vitro biological activities against p21-activated kinase 4. Compounds 11b, 12d and 12g exhibited the most potent inhibitory activity against PAK4 (IC50 = 22 nM, 16 nM and 27 nM, respectively). Among them, compound 12g showed the highest antiproliferative activity against A549 cells (IC50 = 0.83 mu M). Apoptosis analysis in A549 cells suggested that compound 12g delayed cell cycle progression by arresting cells in the G2/M phase of the cell cycle, retarding cell growth. Further investigation demonstrated that compound 12g strongly inhibited migration and invasion of A549 cells. Western blot analysis indicated that compound 12g potently inhibited the PAK4/ LIMK1/cofilin signalling pathways. Finally, the binding mode between compound 12g with PAK4 was proposed by molecular docking. A preliminary ADME profile of the compound 12g was also drawn on the basis of QikProp predictions. (C) 2017 Elsevier Ltd. All rights reserved.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available