Computer-aided identification, synthesis, and biological evaluation of DNA polymerase eta inhibitors for the treatment of cancer

In cancer cells, Pol eta allows DNA replication and cell proliferation even in the presence of chemotherapeutic drug-induced damages, like in the case of platinum-containing drugs. Inhibition of Pol eta thus represents a promising strategy to overcome drug resistance and preserve the effectiveness of chemotherapeutic drugs. Here, we report the discovery of a novel class of Pol n inhibitors, with 35 active close analogs. Compound 21 (ARN24964) stands out as the best inhibitor, with an IC50 value of 14.7 mu M against Pol eta and a good anti -proliferative activity when used in combination with cisplatin - with a synergistic effect in three different cancer cell lines (A375, A549, OVCAR3). Moreover, it is characterized by a favorable drug-like profile in terms of its aqueous kinetic solubility, plasma and metabolic stability. Thus, ARN24964 is a promising compound for further structure-based drug design efforts toward developing drugs to solve or limit the issue of drug resistance to platinum-containing drugs in cancer patients.