Computer-aided identification, synthesis, and biological evaluation of DNA polymerase η 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.

Automated summary

Pol eta plays a crucial role in allowing DNA replication and cell proliferation in cancer cells, even in the presence of chemotherapeutic drug-induced damages. Inhibiting Pol eta could potentially overcome drug resistance and enhance the effectiveness of platinum-containing drugs. This study reports the discovery of a new class of Pol n inhibitors, with compound 21 (ARN24964) showing the best inhibitory activity and synergistic effect with cisplatin in multiple cancer cell lines. Furthermore, ARN24964 possesses favorable drug-like properties, making it a promising candidate for further drug development efforts against drug resistance in cancer patients receiving platinum-containing drugs.