Exploiting the nucleotide substrate specificity of repair DNA polymerases to develop novel anticancer agents

Abstract

The genome is constantly exposed to mutations that can originate during replication or as a result of the action of both endogenous and/or exogenous damaging agents [such as reactive oxygen species (ROS), UV light, genotoxic environmental compounds, etc.]. Cells have developed a set of specialized mechanisms to counteract this mutational burden. Many cancer cells have defects in one or more DNA repair pathways, hence they rely on a narrower set of specialized DNA repair mechanisms than normal cells. Inhibiting one of these pathways in the context of an already DNA repair-deficient genetic background, will be more toxic to cancer cells than to normal cells, a concept recently exploited in cancer chemotherapy by the synthetic lethality approach. Essential to all DNA repair pathways are the DNA pols. Thus, these enzymes are being regarded as attractive targets for the development of specific inhibitors of DNA repair in cancer cells. In this review we examine the current state-of-the-art in the development of nucleotide analogs as inhibitors of repair DNA polymerases.

Figure 1

The “synthetic lethality” system represents a new therapeutic approach for selectively killing of cancer cells. Often cancer cells are deficient in specific DNA repair pathways or factors. (a) When cells are affected by DNA damages, specific DNA pols are activated that allow both normal or cancer cells to survive. (b) In the presence of specific DNA pols inhibitors, cells are not able to repair a DNA damage, which often causes SSBs and DSBs. Normal cells could bypass this problem since they have specific pathways available, instead inhibition of repair DNA pols in cancer cells that are defective in DSBs repair will result in synthetic lethality.

Figure 2

Structures of morpholinonucleoside triphosphates.

Figure 3

Structures of nucleoside triphosphate analogs modified at the β and/or γ-phosphate.

Figure 4

Structures of dinucleoside tri- and tetraphosphates analogs.

Figure 5

Structures of nucleoside and non-nucleoside triphosphate analogs efficiently pairing with AP site. (a) Pyrene nucleotide (dPTP); (b) 4-O-benzoyloxylbutyl triphosphate; (c) (biphenylcarboxyl)-4-oxybutyl triphosphate.