title: First Cdc7 kinase inhibitors: pyrrolopyridinones as potent and orally active antitumor agents. 2. Lead discovery.
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.
authors.affiliation: Nerviano Medical Sciences Srl, Viale Pasteur 10, 20014 Nerviano, Milano, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Menichincheri
authors.forename: Alberto
authors.initials: A
authors.lastname: Bargiotti
authors.forename: Jens
authors.initials: J
authors.lastname: Berthelsen
authors.forename: Jay A
authors.initials: JA
authors.lastname: Bertrand
authors.forename: Roberto
authors.initials: R
authors.lastname: Bossi
authors.forename: Antonella
authors.initials: A
authors.lastname: Ciavolella
authors.forename: Alessandra
authors.initials: A
authors.lastname: Cirla
authors.forename: Cinzia
authors.initials: C
authors.lastname: Cristiani
authors.forename: Valter
authors.initials: V
authors.lastname: Croci
authors.forename: Roberto
authors.initials: R
authors.lastname: D'Alessio
authors.forename: Marina
authors.initials: M
authors.lastname: Fasolini
authors.forename: Francesco
authors.initials: F
authors.lastname: Fiorentini
authors.forename: Barbara
authors.initials: B
authors.lastname: Forte
authors.forename: Antonella
authors.initials: A
authors.lastname: Isacchi
authors.forename: Katia
authors.initials: K
authors.lastname: Martina
authors.forename: Antonio
authors.initials: A
authors.lastname: Molinari
authors.forename: Alessia
authors.initials: A
authors.lastname: Montagnoli
authors.forename: Paolo
authors.initials: P
authors.lastname: Orsini
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Orzi
authors.forename: Enrico
authors.initials: E
authors.lastname: Pesenti
authors.forename: Daniele
authors.initials: D
authors.lastname: Pezzetta
authors.forename: Antonio
authors.initials: A
authors.lastname: Pillan
authors.forename: Italo
authors.initials: I
authors.lastname: Poggesi
authors.forename: Fulvia
authors.initials: F
authors.lastname: Roletto
authors.forename: Alessandra
authors.initials: A
authors.lastname: Scolaro
authors.forename: Marco
authors.initials: M
authors.lastname: Tatò
authors.forename: Marcellino
authors.initials: M
authors.lastname: Tibolla
authors.forename: Barbara
authors.initials: B
authors.lastname: Valsasina
authors.forename: Mario
authors.initials: M
authors.lastname: Varasi
authors.forename: Daniele
authors.initials: D
authors.lastname: Volpi
authors.forename: Corrado
authors.initials: C
authors.lastname: Santocanale
authors.forename: Ermes
authors.initials: E
authors.lastname: Vanotti
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D055808:Drug Discovery; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011728:Pyridones / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D021241:Spectrometry, Mass, Electrospray Ionization; D013056:Spectrophotometry, Ultraviolet; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D047428:Protein Kinase Inhibitors; D011728:Pyridones; C068619:CDC7 protein, human; D017346:Protein Serine-Threonine Kinases