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Cdc7 kinase inhibitors: 5-heteroaryl-3-carboxamido-2-aryl pyrroles as potential antitumor agents. 1. Lead finding. 2010
Maria Menichincheri, and
Clara Albanese, and
Cristina Alli, and
Dario Ballinari, and
Alberto Bargiotti, and
Marina Caldarelli, and
Antonella Ciavolella, and
Alessandra Cirla, and
Maristella Colombo, and
Francesco Colotta, and
Valter Croci, and
Roberto D'Alessio, and
Matteo D'Anello, and
Antonella Ermoli, and
Francesco Fiorentini, and
Barbara Forte, and
Arturo Galvani, and
Patrizia Giordano, and
Antonella Isacchi, and
Katia Martina, and
Antonio Molinari, and
Jürgen K Moll, and
Alessia Montagnoli, and
Paolo Orsini, and
Fabrizio Orzi, and
Enrico Pesenti, and
Antonio Pillan, and
Fulvia Roletto, and
Alessandra Scolaro, and
Marco Tatò, and
Marcellino Tibolla, and
Barbara Valsasina, and
Mario Varasi, and
Paola Vianello, and
Daniele Volpi, and
Corrado Santocanale, and
Ermes Vanotti
Nerviano Medical Sciences Srl, Business Unit Oncology, Viale Pasteur 10, 20014 Nerviano, MI, Italy. maria.menichincheri@nervianoms.com
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.
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Alessandra Cirla, and
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Fabrizio Orzi, and
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