Modern cancer therapies, mainly ionizing radiation and certain classes of chemotherapies target DNA. Although
these treatments disrupt the genome, their rationale is clear. They prevent cancer cells from dividing and proliferating.
Nevertheless, cancer cells can survive by over-activating a wide range of DNA repair pathways to eliminate the induced
damage. In this context, DNA repair mechanisms are considered to be a vital target to improve cancer therapy and
reduce the resistance to many DNA damaging agents currently in use as standard-of-care treatments. Here, we focus on
two important DNA repair pathways, namely base excision repair (BER) and nucleotide excision repair (NER). Specifically,
our focus is on two protein targets that are linked to the hallmark “relapse” and “drug resistance” phenomena. These
are Excision Repair Cross-Complementation Group 1 (ERCC1), and DNA polymerase beta (pol β). The former is a key
player in NER, while the latter is the error-prone polymerase of BER. Our objective is to list all known inhibitors for the
two targets and provide an overview of the great efforts that were made in their discovery. While in the DNA pol β case
more than sixty inhibitors were identified, very few inhibitors have been discovered on the ERCC1 side. It is hoped that
this review will assist in the discovery of novel, potent and specific drug candidates aimed at improving existing cancer
therapies including ionizing radiation, bleomycin, monofunctional alkylating agents and cisplatin.
Keywords: DNA damaging agents, BER, NER, DNA polymerase beta, cancer, inhibitor, ERCC1, XPF, XPA, ionizing radiation, c hemotherapies target DNA
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