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The potential of PARPs within cancer drug discovery

Published 3 June 2024 by Sean Butler

What Are PARPs?

Poly (ADP-ribose) polymerases, commonly known as PARPs, have become a significant focal point in scientific research due to their critical role in cellular processes and potential implications in various diseases. Understanding PARPs and their functions can lead to breakthroughs in cancer treatment, neurodegenerative diseases, and personalised medicine.

PARPs are a family of enzymes involved in a variety of cellular processes, including DNA repair, genomic stability, and programmed cell death. They modify proteins by adding ADP-ribose polymers, a process known as ADP-ribosylation. This modification can affect protein function, interactions, and localisation, which in turn influences cell fate and function.

The role of PARPs in DNA repair

One of the most critical functions of PARPs is their role in DNA repair. When DNA damage occurs, PARPs detect the damage and initiate repair processes. PARP-1, the most studied member of this enzyme family, quickly binds to sites of single-strand breaks and facilitates their repair by recruiting other DNA repair proteins. This function is crucial for maintaining genomic stability and preventing mutations that can lead to cancer.

PARPs and cancer

The link between PARPs and cancer has garnered significant attention. Cancer cells often have high levels of DNA damage and rely on efficient repair mechanisms to survive and proliferate. PARP inhibitors, a class of drugs that block PARP activity, have shown promise in treating cancers with deficiencies in other DNA repair pathways, such as BRCA1 or BRCA2 mutations. By inhibiting PARP activity, these drugs can induce synthetic lethality, selectively killing cancer cells while sparing normal cells. This therapeutic strategy has led to the development of several PARP inhibitors, some of which are already approved for clinical use in treating ovarian, breast, and prostate cancers.

PARP experts BPS Bioscience, have developed a range of assay kits designed to detect and quantify PARP-mediated ribosylation activity within cell extracts to determine whether PARP inhibition can possibly be exploited.

Neurodegenerative diseases

Beyond oncology, PARPs are also implicated in neurodegenerative diseases such as Alzheimer's and Parkinson's. Excessive activation of PARP-1 can lead to cell death and neuroinflammation, contributing to the progression of these diseases. Understanding how PARPs influence neuronal cell death and survival can offer new therapeutic targets for slowing down or preventing neurodegeneration.

Personalised medicine

The growing field of personalised medicine also benefits from PARP research. By understanding an individual’s genetic makeup, particularly mutations in DNA repair genes, clinicians can predict the efficacy of PARP inhibitors and tailor treatments accordingly. This approach ensures that patients receive the most effective therapies based on their unique genetic profiles, enhancing treatment outcomes and minimising side effects.

The PARP2 affinity issue

The development of PARP inhibitors with greater affinity for PARP2 compared to PARP1 can lead to distinct side effects due to the differential roles these enzymes play in cellular processes. While PARP1 is primarily involved in the immediate response to DNA damage, PARP2 plays a more specialised role in DNA repair, chromatin structure, and transcription regulation. Inhibiting PARP2 more selectively might disrupt these critical functions, potentially leading to hematological toxicities, such as anemia or thrombocytopenia, as well as gastrointestinal disturbances, due to its involvement in maintaining the integrity of rapidly dividing cells. Moreover, because PARP2 is also involved in the regulation of gene expression, its inhibition could lead to broader and more unpredictable off-target effects, impacting various physiological systems and potentially causing more severe or chronic conditions. Therefore, understanding and monitoring these side effects is crucial for the safe and effective use of PARP2-selective inhibitors in clinical settings.

BPS Bioscience have also developed the PARPtrap™ Combo Assay Kit for PARP1 and PARP2, which evaluates a molecule’s ability to trap both PARP1 and PARP2 within the same assay - an important feature due to the harsher side effects of PARP2 inhibition. Being able to prove your molecule of interest has a greater PARP1 affinity is crucial, making this innovative research tool a must for PARP researchers.

Future Directions

The future of PARP research is promising, with ongoing studies exploring new PARP inhibitors, combination therapies, and the broader implications of PARP activity in various diseases. Scientists are also investigating the roles of lesser-known PARP family members to uncover their specific functions and potential therapeutic targets.

The future of PARP research is bright with BPS Bioscience

PARPs are a cornerstone of current scientific research due to their fundamental role in DNA repair and their implications in cancer, neurodegenerative diseases, and personalised medicine. By continuing to unravel the complexities of PARP functions, researchers can develop innovative treatments and improve patient outcomes across a range of conditions. With innovative tools such as those courtesy of BPS Bioscience being used to combat the challenges discussed, and as our understanding of PARPs deepens, the potential for groundbreaking discoveries in medicine grows ever larger, making this an exciting and pivotal area of study in the scientific community.

Cell & gene therapy