Impaired DNA repair activity has been shown to greatly increase rates of
cancer clinically. It has been hypothesized that upregulating repair activity in susceptible individuals may be a useful strategy for inhibiting
tumorigenesis. Here, we report that selected
tyrosine kinase (TK) inhibitors including
nilotinib, employed clinically in the treatment of
chronic myeloid leukemia, are activators of the repair
enzyme Human MutT Homolog 1 (MTH1). MTH1 cleanses the oxidatively damaged cellular
nucleotide pool by hydrolyzing the oxidized
nucleotide 8-oxo-2'-deoxyguanosine (8-oxo-dG)TP, which is a highly mutagenic lesion when incorporated into
DNA. Structural optimization of analogues of TK inhibitors resulted in compounds such as SU0448, which induces 1000 ± 100% activation of MTH1
at 10 μM and 410 ± 60% at 5 μM. The compounds are found to increase the activity of the endogenous
enzyme, and at least one (SU0448) decreases levels of
8-oxo-dG in cellular
DNA. The results suggest the possibility of using MTH1 activators to decrease the frequency of mutagenic
nucleotides entering
DNA, which may be a promising strategy to suppress
tumorigenesis in individuals with elevated
cancer risks.