Cdc7 kinase inhibitors: 7-Substituted pyrrolopyridinones as potent and orally active antitumor agents

A224 The Cell Division Cycle 7 (Cdc7) kinase plays a pivotal role in regulating DNA replication in eukaryotic organisms. Inhibition of Cdc7 kinase by both siRNAs and small molecule inhibitors (Montagnoli et al., 2007 AACR Annual Meeting, April 14-18 2007, Los Angeles, CA) causes p53 independent tumor cell death, while it only causes reversible cell cycle arrest in primary fibroblasts supporting the rationale for the development of Cdc7 kinase inhibitors as antitumor agents.
 Starting from 2-pyridin-4-yl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one 1a (IC50 = 10 nM in a Cdc7/Dbf4 kinase assay and greater than 20-fold selectivity vs a panel of other kinases), a strictly related analog 1b was obtained and also proved to be a promising scaffold for Cdc7 inhibition (IC50 = 7 nM in a Cdc7/Dbf4 kinase assay and greater than 40-fold selectivity vs a panel of other kinases).
 In this poster we present the synthesis, structure-activity relationships (SAR) investigation, and biological data of analogues derived from the two compounds 1a and 1b . In particular the SAR studies revealed that position 7 of both compounds could be profitably substituted to yield potent Cdc7 inhibitors. Among those compounds, derivative 8b (S) inhibited Cdc7/Dbf4 kinase with IC 50 = 2 nM with greater than 60-fold selectivity vs a panel of kinases, and hampered tumor cell proliferation of different cell lines with an IC 50 in the submicromolar range. 24h treatment of A2780 ovary carcinoma cells with cpd 8b (S) induced inhibition of Ser40-Mcm2 phosphorylation and apoptosis. Due to its favourable PK profile, the antitumor activity of this compound was evaluated in a A2780 xenograft model by oral administration (60mg/Kg bid, 10d) yielding a TGI = 68% with evidences of target inhibition in tumors. Finally in DMBA induced mammary carcinoma in rats, compound 8b (S) orally administered (20mg/kg bid, 10d) displayed durable tumor stabilisation.