title: Cdc7 kinase inhibitors: 5-heteroaryl-3-carboxamido-2-aryl pyrroles as potential antitumor agents. 1. Lead finding.
abstract: 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.
authors.affiliation: Nerviano Medical Sciences Srl, Business Unit Oncology, Viale Pasteur 10, 20014 Nerviano, MI, Italy. maria.menichincheri@nervianoms.com
authors.forename: Maria
authors.initials: M
authors.lastname: Menichincheri
authors.forename: Clara
authors.initials: C
authors.lastname: Albanese
authors.forename: Cristina
authors.initials: C
authors.lastname: Alli
authors.forename: Dario
authors.initials: D
authors.lastname: Ballinari
authors.forename: Alberto
authors.initials: A
authors.lastname: Bargiotti
authors.forename: Marina
authors.initials: M
authors.lastname: Caldarelli
authors.forename: Antonella
authors.initials: A
authors.lastname: Ciavolella
authors.forename: Alessandra
authors.initials: A
authors.lastname: Cirla
authors.forename: Maristella
authors.initials: M
authors.lastname: Colombo
authors.forename: Francesco
authors.initials: F
authors.lastname: Colotta
authors.forename: Valter
authors.initials: V
authors.lastname: Croci
authors.forename: Roberto
authors.initials: R
authors.lastname: D'Alessio
authors.forename: Matteo
authors.initials: M
authors.lastname: D'Anello
authors.forename: Antonella
authors.initials: A
authors.lastname: Ermoli
authors.forename: Francesco
authors.initials: F
authors.lastname: Fiorentini
authors.forename: Barbara
authors.initials: B
authors.lastname: Forte
authors.forename: Arturo
authors.initials: A
authors.lastname: Galvani
authors.forename: Patrizia
authors.initials: P
authors.lastname: Giordano
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: Jürgen K
authors.initials: JK
authors.lastname: Moll
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: Antonio
authors.initials: A
authors.lastname: Pillan
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: Paola
authors.initials: P
authors.lastname: Vianello
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: 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
chemical_list: 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