Synthesis and structure–activity relationship of trisubstituted thiazoles as Cdc7 kinase inhibitors

• Inhibition of Cdc7 kinase may not be limited by cytotoxicity to regular cells.
• Compounds with low MW and high binding efficiencies were found in the HTS.
• Our SAR studies systematically explored all substituents on the core of thiazoles.
• We discovered selective Cdc7 inhibitors that showed potency in vitro and in vivo.
• The synthesis of every compound in this manuscript is illustrated.

The Cell division cycle 7 (Cdc7) protein kinase is essential for DNA replication and maintenance of genome stability. We systematically explored thiazole-based compounds as inhibitors of Cdc7 kinase activity in cancer cells. Our studies resulted in the identification of a potent, selective Cdc7 inhibitor that decreased phosphorylation of the direct substrate MCM2 in vitro and in vivo, and inhibited DNA synthesis and cell viability in vitro.

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