• Both compounds show single agent activity and accumulation of DSBs and formation of stalled replication forks.• NSC 19630 sensitizes cells to G-quadruplex-binding compound telomestatin, or PARP inhibitor by inducing synthetic lethality.• NSC 617145 induces WRN binding to chromatin and proteasomal degradation, enhances Fanconi Anemia (FA) mutated cells activity to MMC and activates ATM by inducing synthetic lethality.IC50 = 2-5 μM. This evidence concerns the gene WRN and Friedreich ataxia.