Cdc7 kinase inhibitors: 5-heteroaryl-3-carboxamido-2-aryl pyrroles as potential antitumor agents. 1. Lead finding.
Cdc7 serine/threonine kinase is a key regulator of DNA synthesis in eukaryotic organisms. Cdc7 inhibition through siRNA or prototype small molecules causes p53 independent apoptosis in tumor cells while reversibly arresting cell cycle progression in primary fibroblasts. This implies that Cdc7 kinase could be considered a potential target for anticancer therapy. We previously reported that pyrrolopyridinones (e.g., 1) are potent and selective inhibitors of Cdc7 kinase, with good cellular potency and in vitro ADME properties but with suboptimal pharmacokinetic profiles. Here we report on a new chemical class of 5-heteroaryl-3-carboxamido-2-substituted pyrroles (1A) that offers advantages of chemistry diversification and synthetic simplification. This work led to the identification of compound 18, with biochemical data and ADME profile similar to those of compound 1 but characterized by superior efficacy in an in vivo model. Derivative 18 represents a new lead compound worthy of further investigation toward the ultimate goal of identifying a clinical candidate.
Menichincheri
Maria
M
Nerviano Medical Sciences Srl, Business Unit Oncology, Viale Pasteur 10, 20014 Nerviano, MI, Italy. maria.menichincheri@nervianoms.com
Albanese
Clara
C
Alli
Cristina
C
Ballinari
Dario
D
Bargiotti
Alberto
A
Caldarelli
Marina
M
Ciavolella
Antonella
A
Cirla
Alessandra
A
Colombo
Maristella
M
Colotta
Francesco
F
Croci
Valter
V
D'Alessio
Roberto
R
D'Anello
Matteo
M
Ermoli
Antonella
A
Fiorentini
Francesco
F
Forte
Barbara
B
Galvani
Arturo
A
Giordano
Patrizia
P
Isacchi
Antonella
A
Martina
Katia
K
Molinari
Antonio
A
Moll
Jürgen K
JK
Montagnoli
Alessia
A
Orsini
Paolo
P
Orzi
Fabrizio
F
Pesenti
Enrico
E
Pillan
Antonio
A
Roletto
Fulvia
F
Scolaro
Alessandra
A
Tatò
Marco
M
Tibolla
Marcellino
M
Valsasina
Barbara
B
Varasi
Mario
M
Vianello
Paola
P
Volpi
Daniele
D
Santocanale
Corrado
C
Vanotti
Ermes
E
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001682:Biological Availability; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous
C553259:5-(2-amino-pyrimidin-4-yl)-2-phenyl-1H-pyrrole-3-carboxamide; D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D011743:Pyrimidines; D011758:Pyrroles; C068619:CDC7 protein, human; C489403:Cdc7 protein, mouse; D017346:Protein Serine-Threonine Kinases