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.

Synthesis, Modeling, and RET Protein Kinase Inhibitory Activity of 3-and 4-Substituted beta-Carbolin-1-ones

TUCCINARDI, TIZIANO;MARTINELLI, ADRIANO;
2008

Abstract

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.
Cincinelli, Raffaella; Cassinelli, Giuliana; Dallavalle, Sabrina; Lanzi, Cinzia; Merlini, Lucio; Botta, Maurizio; Tuccinardi, Tiziano; Martinelli, Adriano; Penco, Sergio; Zunino, Franco
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11568/203703
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