First Cdc7 kinase inhibitors: pyrrolopyridinones as potent and orally active antitumor agents. 2. Lead discovery

  • J Med Chem. 2009 Jan 22;52(2):293-307. doi: 10.1021/jm800977q.
Maria Menichincheri  1 ,  Alberto Bargiotti ,  Jens Berthelsen ,  Jay A Bertrand ,  Roberto Bossi ,  Antonella Ciavolella ,  Alessandra Cirla ,  Cinzia Cristiani ,  Valter Croci ,  Roberto D'Alessio ,  Marina Fasolini ,  Francesco Fiorentini ,  Barbara Forte ,  Antonella Isacchi ,  Katia Martina ,  Antonio Molinari ,  Alessia Montagnoli ,  Paolo Orsini ,  Fabrizio Orzi ,  Enrico Pesenti ,  Daniele Pezzetta ,  Antonio Pillan ,  Italo Poggesi ,  Fulvia Roletto ,  Alessandra Scolaro ,  Marco Tatò ,  Marcellino Tibolla ,  Barbara Valsasina ,  Mario Varasi ,  Daniele Volpi ,  Corrado Santocanale ,  Ermes Vanotti
Affiliations
  • 1. Nerviano Medical Sciences Srl, Viale Pasteur 10, 20014 Nerviano, Milano, Italy.
PMID: 19115845 DOI: 10.1021/jm800977q
Abstract

CDC7 kinase is a key regulator of the S-phase of the cell cycle, known to promote the activation of DNA replication origins in eukaryotic organisms. CDC7 inhibition can cause tumor-cell death in a p53-independent manner, supporting the rationale for developing CDC7 inhibitors for the treatment of Cancer. In this paper, we conclude the structure-activity relationships study of the 2-heteroaryl-pyrrolopyridinone class of compounds that display potent inhibitory activity against CDC7 kinase. Furthermore, we also describe the discovery of 89S, [(S)-2-(2-aminopyrimidin-4-yl)-7-(2-fluoro-ethyl)-1,5,6,7-tetrahydropyrrolo[3,2-c]pyridin-4-one], as a potent ATP mimetic inhibitor of CDC7. Compound 89S has a Ki value of 0.5 nM, inhibits cell proliferation of different tumor cell lines with an IC50 in the submicromolar range, and exhibits in vivo tumor growth inhibition of 68% in the A2780 xenograft model.