Paper Info
Title
Identification and Preliminary SAR Analysis of Novel Type-I Inhibitors of TIE-2 via Structure-Based Virtual Screening and Biological Evaluation in in vitro Models.
Abstract
Angiopoietin (ANG) ligands and their downstream TIE receptors have been validated as the second vascular signaling system involving vessel remodeling and maturation. Among them, the ANG/TIE-2 signaling pathway is involved in numerous life-threatening diseases and has become an attractive potential therapeutic target. Several large-molecule inhibitors targeting the ANG/TIE-2 axis have recently entered clinical phase for the therapy of various solid tumors, but selective small-molecule inhibitors of TIE-2 are still quite limited. In the present work, structure-based virtual screening was performed to search for type-I inhibitors of TIE-2. Of the only 41 compounds selected by our strategy, 8 molecules with the concentration of 25 mu g/mL exhibit over 50% inhibitory rate against TIE-2 in in vitro enzymatic activity assay, and the IC50 values of 2 hits are lower than 1 mu M. Further optimization and SAR analysis based on compound TP-S1-30 and 31 were carried out by using substructure searching strategy, leading to the discovery of several sub-100 nM inhibitors. Among them, the most potent compound, TP-S1-68, showed an inhibitory IC50 of 0.149 mu M. These novel inhibitors of TIE-2 discovered in this study and the analogs of the active core scaffolds can serve as the starting points for further drug development.
Year
DOI
Venue
2015
10.1021/acs.jcim.5b00576
JOURNAL OF CHEMICAL INFORMATION AND MODELING
Field
DocType
Volume
IC50,Enzyme,In vitro,Chemistry,Signal transduction,Angiopoietin,Structure–activity relationship,Bioinformatics,Virtual screening,Enzyme activator
Journal
55
Issue
ISSN
Citations 
12
1549-9596
0
PageRank 
References 
Authors
0.34
10
8
Name
Order
Citations
PageRank
Peichen Pan100.68
Sheng Tian2333.67
Huiyong Sun3346.09
Xiaotian Kong400.68
Wenfang Zhou501.01
Dan Li6266.82
Youyong Li723818.54
Tingjun Hou842754.50