Inhibition of human DNA polymerases eta and kappa by indole-derived molecules occurs through distinct mechanisms

Overexpression of human DNA polymerase kappa (hpol κ) in glioblastoma is associated with shorter survival time and resistance to the alkylating agent temozolomide (TMZ), making it an attractive target for the development of small-molecule inhibitors. We previously reported on the development and characterization of indole barbituric acid-derived (IBA) inhibitors of translesion DNA synthesis polymerases (TLS pols). We have now identified a potent and selective inhibitor of hpol κ based on the indole-aminoguanidine (IAG) chemical scaffold. The most promising IAG analog, IAG-10, exhibited greater inhibitory action against hpol κ than any other human Y-family member, as well as pols from the A-, B-, and X-families. Inhibition of hpol κ by IAG analogs appears to proceed through a mechanism that is distinct from inhibition of hpol η, based on changes in DNA binding affinity and nucleotide insertion kinetics. By way of comparison, both IAG and IBA analogs inhibited binary complex formation by hpol κ and ternary ...