Synthesis and investigation of thieno[2,3-b]pyridines that restore activity of topotecan†

Chemoresistance poses a major challenge to the successful outcome of cancer chemotherapy by reducing or eliminating drug efficacy. Anti-cancer medicines causing DNA damage by inhibiting topoisomerase I (TOP1) are particularly susceptible as cancers adopt resistance mechanisms. Drugs countering these resistance mechanisms can be introduced to the regimen and increase the vulnerability of cancer cells to TOP1 inhibitors. DNA repair enzymes such as tyrosyl-DNA phosphodiesterase 1 (TDP1) emerge as promising drug targets for restoring activity of TOP1 inhibitors. Herein, we describe the synthesis and biological evaluation of thieno[2,3-b]pyridines that markedly sensitised H460 lung cancer cells to the TOP1 inhibitor topotecan. Surprisingly, TDP1 knockout further potentiated the synergy between thieno[2,3-b]pyridines and topotecan suggesting that a complex network of DNA repair pathways rather than TDP1 alone mediates the sensitising effect. SAR studies have identified structural motifs in this compound class that led to optimal performance, identifying leads for development into clinical chemosensitisers of TOP1 poisons.