First Cdc7 kinase inhibitors: pyrrolopyridinones as potent and orally active antitumor agents. 2. Lead discovery.
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.
Menichincheri
Maria
M
Nerviano Medical Sciences Srl, Viale Pasteur 10, 20014 Nerviano, Milano, Italy.
Bargiotti
Alberto
A
Berthelsen
Jens
J
Bertrand
Jay A
JA
Bossi
Roberto
R
Ciavolella
Antonella
A
Cirla
Alessandra
A
Cristiani
Cinzia
C
Croci
Valter
V
D'Alessio
Roberto
R
Fasolini
Marina
M
Fiorentini
Francesco
F
Forte
Barbara
B
Isacchi
Antonella
A
Martina
Katia
K
Molinari
Antonio
A
Montagnoli
Alessia
A
Orsini
Paolo
P
Orzi
Fabrizio
F
Pesenti
Enrico
E
Pezzetta
Daniele
D
Pillan
Antonio
A
Poggesi
Italo
I
Roletto
Fulvia
F
Scolaro
Alessandra
A
Tatò
Marco
M
Tibolla
Marcellino
M
Valsasina
Barbara
B
Varasi
Mario
M
Volpi
Daniele
D
Santocanale
Corrado
C
Vanotti
Ermes
E
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
D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D047428:Protein Kinase Inhibitors; D011728:Pyridones; C068619:CDC7 protein, human; D017346:Protein Serine-Threonine Kinases