Dehydroaltenusin is a specific inhibitor of mammalian DNA polymerase α

Abstract

Introduction: We carried out a screen for small molecule selective inhibitors of eukaryotic DNA polymerases (pols). Dehydroaltenusin, isolated from a fungus (Alternaria tenuis), was found to be a specific inhibitor of pol α.

Areas covered: We succeeded in chemically synthesizing dehydroaltenusin along with five analogs. Of these compounds, dehydroaltenusin was the strongest and most specific inhibitor of mammalian pol α, with an IC₅₀ value of 0.68 μM. The inhibitory mode of action of dehydroaltenusin against mammalian pol α activity was competitive with respect to the DNA template primer and non-competitive with respect to the 2′-deoxyribonucleoside 5′-triphosphate substrate. Dehydroaltenusin inhibited the cell proliferation of a human cervical cancer cell line, HeLa, by arresting the cells at the S-phase, and preventing the incorporation of thymidine into the cells. These observations indicate that dehydroaltenusin blocks in vivo DNA replication by inhibiting pol α.

Expert opinion: Dehydroaltenusin was effective in suppressing the growth of solid tumors and, therefore, is of interest as a candidate drug for anti-cancer treatment.

Keywords:

• anti-tumor effect
• apoptosis
• cell proliferation
• cytotoxicity
• dehydroaltenusin
• DNA polymerase α
• DNA replication
• enzyme inhibitor

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