Cdc7 kinase inhibitors: pyrrolopyridinones as potential antitumor agents. 1. Synthesis and structure-activity relationships.
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.
Vanotti
Ermes
E
Nerviano Medical Sciences Srl, Viale Pasteur 10, 20014 Nerviano, Milano, Italy. ermes.vanotti@nervianoms.com
Amici
Raffaella
R
Bargiotti
Alberto
A
Berthelsen
Jens
J
Bosotti
Roberta
R
Ciavolella
Antonella
A
Cirla
Alessandra
A
Cristiani
Cinzia
C
D'Alessio
Roberto
R
Forte
Barbara
B
Isacchi
Antonella
A
Martina
Katia
K
Menichincheri
Maria
M
Molinari
Antonio
A
Montagnoli
Alessia
A
Orsini
Paolo
P
Pillan
Antonio
A
Roletto
Fulvia
F
Scolaro
Alessandra
A
Tibolla
Marcellino
M
Valsasina
Barbara
B
Varasi
Mario
M
Volpi
Daniele
D
Santocanale
Corrado
C
D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D005663:Furans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011728:Pyridones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D005663:Furans; D011728:Pyridones; D011758:Pyrroles; C068619:CDC7 protein, human; D017346:Protein Serine-Threonine Kinases