Cdc7 kinase inhibitors: pyrrolopyridinones as potential antitumor agents. 1. Synthesis and structure-activity relationships

  • J Med Chem. 2008 Feb 14;51(3):487-501. doi: 10.1021/jm700956r.
Ermes Vanotti  1 ,  Raffaella Amici ,  Alberto Bargiotti ,  Jens Berthelsen ,  Roberta Bosotti ,  Antonella Ciavolella ,  Alessandra Cirla ,  Cinzia Cristiani ,  Roberto D'Alessio ,  Barbara Forte ,  Antonella Isacchi ,  Katia Martina ,  Maria Menichincheri ,  Antonio Molinari ,  Alessia Montagnoli ,  Paolo Orsini ,  Antonio Pillan ,  Fulvia Roletto ,  Alessandra Scolaro ,  Marcellino Tibolla ,  Barbara Valsasina ,  Mario Varasi ,  Daniele Volpi ,  Corrado Santocanale
Affiliations
  • 1. Nerviano Medical Sciences Srl, Viale Pasteur 10, 20014 Nerviano, Milano, Italy. [email protected]
PMID: 18201066 DOI: 10.1021/jm700956r
Abstract

Cdc7 kinase is an essential protein that promotes DNA replication in eukaryotic organisms. Genetic evidence indicates that Cdc7 inhibition can cause selective tumor-cell death in a p53-independent manner, supporting the rationale for developing Cdc7 small-molecule inhibitors for the treatment of cancers. In this paper, the synthesis and structure-activity relationships of 2-heteroaryl-pyrrolopyridinones, the first potent Cdc7 kinase inhibitors, are described. Starting from 2-pyridin-4-yl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one, progress toward a simple scaffold, tailored for Cdc7 inhibition, is reported.