A series of beta-carbolin-2-ones and 3,10-dihydro-2H-azepino[3,4-b]indol-1-ones have been designed, synthesized, and evaluated as RET protein kinase inhibitors oil the basis Of their Structural similarity with the prototype indolin-2-one RPI-1. Some beta-carbolin-2-ones (structure 2) showed ail ability to inhibit RET enzymatic activity in vitro and proliferation of RETC634R oncogene-transformed NIH3T3 cells comparable to that of the reference compound. The docking analysis of the interaction of these compounds with the crystallographic structure of RET tyrosine kinase domain suggested a new binding interaction scheme different from the one proposed during their design. The rigid structure of the compounds of this series represents a new scaffold with potential advantages in the design of RET protein kinase inhibitors.
|Titolo:||Synthesis, Modeling, and RET Protein Kinase Inhibitory Activity of 3- and 4-Substituted β-Carbolin-1-ones|
CINCINELLI, RAFFAELLA (Primo)
|Parole Chiave:||MEDULLARY-THYROID CARCINOMA ; RET/PTC1 ONCOPROTEIN ; CELL-PROLIFERATION ; CANCER ; RPI-1 ; RECEPTOR ; THERAPY ; DOMAIN ; SELECTIVITY ; VALIDATION|
|Settore Scientifico Disciplinare:||Settore CHIM/06 - Chimica Organica|
|Data di pubblicazione:||25-dic-2008|
|Digital Object Identifier (DOI):||10.1021/jm8007823|
|Appare nelle tipologie:||01 - Articolo su periodico|