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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.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Menichincheri M,Albanese C,Alli C,Ballinari D,Bargiotti A,Caldarelli M,Ciavolella A,Cirla A,Colombo M,Colotta F,Croci V,D'Alessio R,D'Anello M,Ermoli A,Fiorentini F,Forte B,Galvani A,Giordano P,Isacchi A,Martina K,

doi

10.1021/jm100504d

subject

Has Abstract

pub_date

2010-10-28 00:00:00

pages

7296-315

issue

20

eissn

0022-2623

issn

1520-4804

journal_volume

53

pub_type

杂志文章

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