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 μg/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 μM. 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 μM. 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.
authors.forename: Peichen
authors.initials: P
authors.lastname: Pan
authors.affiliation: Institute of Functional Nano and Soft Materials (FUNSOM), Soochow University , Suzhou, Jiangsu 215123, China.
authors.forename: Sheng
authors.initials: S
authors.lastname: Tian
authors.forename: Huiyong
authors.initials: H
authors.lastname: Sun
authors.affiliation: Institute of Functional Nano and Soft Materials (FUNSOM), Soochow University , Suzhou, Jiangsu 215123, China.
authors.forename: Xiaotian
authors.initials: X
authors.lastname: Kong
authors.forename: Wenfang
authors.initials: W
authors.lastname: Zhou
authors.forename: Dan
authors.initials: D
authors.lastname: Li
authors.affiliation: Institute of Functional Nano and Soft Materials (FUNSOM), Soochow University , Suzhou, Jiangsu 215123, China.
authors.forename: Youyong
authors.initials: Y
authors.lastname: Li
authors.forename: Tingjun
authors.initials: T
authors.lastname: Hou
mesh_terms: D001681:Biological Assay; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004789:Enzyme Activation / Q000187:drug effects; D020128:Inhibitory Concentration 50; D062105:Molecular Docking Simulation; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D042787:Receptor, TIE-2 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; D042787:Receptor, TIE-2