Drug design with Cdc7 kinase: a potential novel cancer therapy target

Masaaki Sawa¹, Hisao Masai²

¹Carna Biosciences, Inc., Kobe, Japan; ²Genome Dynamics Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

Abstract: Identification of novel molecular targets is critical in development of new and efficient cancer therapies. Kinases are one of the most common drug targets with a potential for cancer therapy. Cell cycle progression is regulated by a number of kinases, some of which are being developed to treat cancer. Cdc7 is a serine-threonine kinase originally discovered in budding yeast, which has been shown to be necessary to initiate the S phase. Inhibition of Cdc7 in cancer cells retards the progression of the S phase, accumulates DNA damage, and induces p53-independent cell death, but the same treatment in normal cells does not significantly affect viability. Low-molecular-weight compounds that inhibit Cdc7 kinase with an IC₅₀ of less than 10 nM have been identified, and shown to be effective in the inhibition of tumor growth in animal models. Thus Cdc7 kinase can be recognized as a novel molecular target for cancer therapy.

Keywords: Cdc7 kinase, cell cycle, replication fork, genome stability, DNA damages, ATP-binding pocket, kinase inhibitor