PARP Inhibitor Drugs Can Be Modified to Better Kill Tumor Cells

Researchers have struggled to show a poly(ADP-ribose) polymerase—1 (PARP-1) inhibitor drug’s effectiveness in clinical trials against cancers. However, in a new study published in Science, the authors investigated the molecular impact of the cancer-killing PARP-1 inhibitor (PARPi) binding to PARP-1 and found that the drug can be structurally modified to increase its power to kill tumor cells.¹

The researchers also found that that the drug can be fine-tuned to achieve allosteric effects, and to influence PARP-1 retention on DNA damage and trapping on chromatin in cells. These results demonstrated that this class of drugs might potentially be better suited to treat other diseases, such as cardiovascular disease, neurodegenerative diseases, inflammation, and potentially coronavirus disease 2019 (COVID-19), that would benefit from PARP-1 inhibition but not cell death.¹

“We can now use this new understanding of how PARP inhibitors work to design compounds that are better tailored for specific conditions such as cancers vs. heart disease,” said senior author Ben Black, PhD, the Eldridge Reeves Johnson Foundation Professor of Biochemistry and Biophysics and co-director of the Penn Center for Genome Integrity at the Perelman School of Medicine at the University of Pennsylvania, in a press release.²

PARP-1 is an abundant enzyme in the cell nucleus that regulates the repair of genomes by binding to DNA damage sites and creating the poly(ADP-ribose) posttranslational modification. The hyperactivity of PARP-1 can result in cell stress or death, which is associated with diseases such as cardiovascular disease and several common neurodegenerative disorders. In prior clinical trials, researchers also found PARP-1 to be an effective target for some cancers.¹

Clinical PARPi compounds all bind at the same place at the catalytic center of the enzyme to block the binding of substrate nicotinamide adenine dinucleotide (NAD+) and prevent poly(ADP-ribose) production. Yet PARPi compounds have shown vastly different outcomes in the killing of tumor cells and in efficacy. This paradox has confused researchers and limited the development of PARPi in the past.¹

In the study published in Science, the research team concluded that a resolution to this paradox may lie in understanding that the most effective PARPi compounds trap PARP-1 at the site of a DNA break, generating a lesion that becomes cytotoxic, especially in tumor cells with deficiencies in the repair of DNA strand breaks.¹

The research team used techniques in the study that included atomic level structural determination and probing the dynamics of the amide protons of the backbone of PARP-1, which went beyond the limits of previous research on PARPi.¹

Veliparib, a PARPi that has posed difficulties for pharmaceutical researchers due to its lack of success when fighting breast and lung cancers, was found to weaken PARP-1's hold on DNA in the trial. Although this could potentially make it easier for veliparib-treated tumor cells to survive, the research team found that they could chemically modify veliparib to enhance its trapping PARP-1 on DNA. This increased veliparib’s ability to kill different types of cancer cells.¹

“It was clear that the increased potency of the new compound relative to unmodified veliparib is due to its increased ability to keep PARP-1 bound to DNA breaks,” Black said in a press release.²

The results of the study clarified the complex interaction between PARPi and the PARP-1 enzyme, showing how differences in the interaction correspond to varying cell-killing effects. Based on these results, an improved understanding of this interaction can be applied to designing more potent anticancer PARPi in the future, Black explained.²

REFERENCES

• Zandarashvili L, Langelier M, Velagapudi UK, et al. Structural basis for allosteric PARP-1 retention on DNA breaks. Science. 2020;368(6486):eaax6367. doi: 10.1126/science.aax6367.
• PARP inhibitor drugs can be 'tuned' for better killing of tumor cells [news release]. ScienceDaily; 2020. sciencedaily.com/releases/2020/04/200410162426.htm. Accessed April 13, 2020.