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Cdc7 Kinase Inhibitors: 5-Heteroaryl-3-Carboxamido-2-Aryl Pyrroles as Potential Antitumor Agents. 1. Lead Finding

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Maria Menichincheri,*,† Clara Albanese,† Cristina Alli,† Dario Ballinari,† Alberto Bargiotti,† Marina Caldarelli,† Antonella Ciavolella,† Alessandra Cirla,† Maristella Colombo,† Francesco Colotta,† Valter Croci,† Roberto D’Alessio,† Matteo D’Anello,† Antonella Ermoli,† Francesco Fiorentini,‡ Barbara Forte,† Arturo Galvani,† Patrizia Giordano,† Antonella Isacchi,† Katia Martina,†,§ Antonio Molinari,‡ J€ urgen K. Moll,† Alessia Montagnoli,† Paolo Orsini,† Fabrizio Orzi,† † † † Enrico Pesenti, Antonio Pillan, Fulvia Roletto, Alessandra Scolaro,† Marco Tat o,† Marcellino Tibolla,† Barbara Valsasina,† †, †, † †,^ Mario Varasi, Paola Vianello, Daniele Volpi, Corrado Santocanale, and Ermes Vanotti† Nerviano Medical Sciences Srl, Business Unit Oncology, Viale Pasteur 10, 20014 Nerviano (MI), Italy, and ‡Accelera Srl, Viale Pasteur 10, 20014 Nerviano (MI), Italy. §Present address: Universit a degli Studi di Torino, Italy. Present address: IEO European Institute of Oncology, Milan, Italy. ^ Present address: NUI Galway, Ireland. )

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Received April 26, 2010

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.

Introduction The inhibition of DNA synthesis is a well-established strategy in the treatment of hyper-proliferative disorders.1 However, the toxicity and tumor cell resistance associated with current DNA replication inhibitors2 make the discovery of novel agents targeting this process by a different mechanism an urgent need. In eukaryotic cells, DNA synthesis is initiated by multiple origins of replication in the genome.3 Cdc7a is a serine/threonine kinase that promotes the firing of the DNA replication origin by phosphorylating one or more subunits of the MCM DNA helicase complex (MCM2-7), thus leading to the unwinding of double-stranded DNA at the origins of *To whom correspondence should be addressed. Phone: þ390331-581928. Fax: þ39-0331-581347. E-mail: maria.menichincheri@ nervianoms.com. a Ab