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

• DOI: 10.1021/jm100504d
• Publication Date: 2010-09-27T15:49:24Z
• Authors: 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; Jürgen K. Moll; Alessia Montagnoli; Paolo Orsini; Fabrizio Orzi; Enrico Pesenti; Antonio Pillan; Fulvia Roletto; Alessandra Scolaro; Marco Tatò; Marcellino Tibolla; Barbara Valsasina; Mario Varasi; Paola Vianello; Daniele Volpi; Corrado Santocanale; Ermes Vanotti
• Keywords: ADME; Lead compound

Cdc7 serine/threonine kinase is a key regulator of DNA synthesis in eukaryotic organisms. inhibition through siRNA or prototype small molecules causes p53 independent apoptosis tumor cells while reversibly arresting cell cycle progression primary fibroblasts. This implies that could be considered potential target for anticancer therapy. We previously reported pyrrolopyridinones (e.g., 1) are potent and selective inhibitors kinase, with good cellular potency vitro ADME properties but suboptimal pharmacokinetic profiles. Here we report on new chemical class 5-heteroaryl-3-carboxamido-2-substituted pyrroles (1A) offers advantages chemistry diversification synthetic simplification. work led to the identification compound 18, biochemical data profile similar those 1 characterized by superior efficacy an vivo model. Derivative 18 represents lead worthy further investigation toward ultimate goal identifying clinical candidate.