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 on the basis of their structural similarity with the prototype indolin-2-one RPI-1. Some beta-carbolin-2-ones (structure 2) showed an 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.
|Autori:||CINCINELLI RAFFAELLA; CASSINELLI GIULIANA; DALLAVALLE SABRINA; LANZI CINZIA; MERLINI LUCIO; BOTTA MAURIZIO; TUCCINARDI TIZIANO; MARTINELLI A; PENCO SERGIO; ZUNINO FRANCO|
|Titolo:||Synthesis, Modeling, and RET Protein Kinase Inhibitory Activity of 3-and 4-Substituted beta-Carbolin-1-ones|
|Anno del prodotto:||2008|
|Digital Object Identifier (DOI):||10.1021/jm8007823|
|Appare nelle tipologie:||1.1 Articolo in rivista|