5’‐Phosphorylation Increases the Efficacy of Nucleoside Inhibitors of the DNA Repair Enzyme SNM1A

Certain cancers exhibit upregulation of DNA interstrand crosslink repair pathways, which contributes to resistance to crosslinking chemotherapy drugs and poor prognoses. Inhibition of enzymes implicated in interstrand crosslink repair is therefore a promising strategy for improving the efficacy of cancer treatment. One such target enzyme is SNM1A, a zinc co‐ordinating 5’–3’ exonuclease. Previous studies have demonstrated the feasibility of inhibiting SNM1A using modified nucleosides appended with zinc‐binding groups. In this work, we sought to develop more effective SNM1A inhibitors by exploiting interactions with the phosphate‐binding pocket adjacent to the enzyme's active site, in addition to the catalytic zinc ions. A series of nucleoside derivatives bearing phosphate moieties at the 5’‐position, as well as zinc‐binding groups at the 3’‐position, were prepared and tested in gel‐electrophoresis and real‐time fluorescence assays. As well as investigating novel zinc‐binding groups, we found that incorporation of a 5’‐phosphate dramatically increased the potency of the inhibitors. A promising strategy to improve the efficacy of cancer chemotherapy is the inhibition of enzymes implicated in interstrand crosslink repair. One such target enzyme is SNM1A, a zinc‐dependent exonuclease. We prepared several series of nucleoside derivatives and tested these as SNM1A inhibitors. Exploiting interactions with the enzyme's phosphate‐binding pocket, in addition to the catalytic zinc ion(s), dramatically increased inhibitory potency.