DNA Repair Inhibitors: The Next Major Step to Improve Cancer Therapy

Abstract

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.

Irreversible Inhibition of DNA Polymerase β by Small-Molecule Mimics of a DNA Lesion

“…17 To our knowledge, these are the first suicide inhibitors that target the lyase activity of Pol β. Due to the lack of MS evidence, we cannot unequivocally state that the inhibitor modifies the lysine(s) involved in Schiff-base formation.…”

“…Furthermore, the IC 50 of 3a is comparable to the best of previously reported Pol β inhibitors. 17 Importantly, experiments in cell lysates derived from a variety of mouse embryonic fibroblasts lacking neither, one, or both Pol β or Pol λ demonstrate that 18 , which is enzymatically converted to 3a in lysates selectively inhibits the lyase activity of the former over the latter. Although other enzymes that contribute to the lyase reaction of 32 P- 15 are affected more weakly by 18 , overall the experiments involving mouse embryonic fibroblast lysates support inhibition of the targeted Pol β in cells.…”

“…Part of the attraction of Pol β as a potential therapeutic target is that it is over expressed in a variety of cancer cells. 15–17 In addition, Pol β variants are found in a large percentage of tumors. 18–20 Some of the variants exhibit reduced activity and may contribute to tumorigenesis by decreasing genomic stability.…”

Tumor protein D52 represents a negative regulator of ATM protein levels

“…33 On the other hand, DNA repair ability of tumor cells prevents the accumulation of lethal DNA damage from cytotoxic agents and ionizing radiation, which leads to tumor resistance. 34,35 Therefore, DDR plays a central role in tumorigenesis and cancer therapy.…”

A human ether-á-go-go-related (hERG) ion channel atomistic model generated by long supercomputer molecular dynamics simulations and its use in predicting drug cardiotoxicity

“…Root-meansquare deviations (RMSD) and B-factors were computed over the duration of the simulation time using the PTRAJ utility. The 1-D electron density profiles were calculated using the density profile tool as implemented in VMD (Barakat et al, 2012a) for the last 300 ns.…”