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DNA damage and genomic instability are hallmarks of cancer, making the DNA damage response (DDR) pathways an attractive target for cancer therapeutics. One such target is the enzyme Poly(ADP-ribose) polymerase (PARP), which plays a crucial role in various DDR mechanisms. At Alfa Cytology, we provide PARP inhibitor development services for the advanced cancer therapy.
Poly(ADP-ribose) polymerase (PARP) is a family of enzymes that play a crucial role in the DNA damage response (DDR) pathways. Upon DNA damage, PARP enzymes, particularly PARP-1, PARP-2, and PARP-3, become activated and catalyze the addition of poly(ADP-ribose) (PAR) modifications on target proteins. Various forms of cancer are more dependent on PARP than normal cells, making PARP an attractive target for cancer therapy.
Fig. 1 Mechanism of PARP inhibitors for cancer therapy. (Dilmac S., et al. 2023)
PARP inhibitors (PARPi) work by competitively binding to the catalytic domain of PARP enzymes, blocking their enzymatic activity and impairing DNA repair. However, the cytotoxicity of PARPi extends beyond just inhibiting PARP activity. Certain PARPi, such as olaparib, niraparib, and talazoparib, have the ability to trap PARP-1 on DNA, preventing its dissociation and leading to the formation of persistent DNA double-strand breaks. This PARP trapping phenomenon is a key mechanism by which PARPi selectively target cancer cells with deficiencies in homologous recombination (HR) DNA repair, such as those harboring BRCA1/2 mutations.
Ongoing research is exploring the use of PARPi in combination with other therapies, such as chemotherapy, radiation, targeted agents, and immunotherapy. Combination strategies can help overcome resistance by targeting multiple pathways simultaneously, enhance the anti-tumor activity of PARPi, and broaden the spectrum of cancer types that can be treated effectively with these targeted agents.
| NCT | PARP Inhibitor | Immunotherapy | Phase |
| NCT03101280 | Rucaparib | Atezolizumab (PD-1) |
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| NCT02571725 | Olaparib | Tremelimumab (CTLA-4) |
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| NCT02484404 | Olaparib | Atezolizumab (PD-L1) Cediranib (VEGFR) |
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The PARP inhibitor market size is poised for substantial growth, driven by the rising incidence of cancers, the unmet clinical needs, and the relentless pursuit of more effective and personalized therapeutic solutions. Through innovative research and advanced technology, Alfa Cytology delves into the mechanisms of PARP action and has the ability to help clients develop novel PARP inhibitors, as well as optimize the effectiveness of PARP inhibitors and identify their biomarkers, to accelerate the development of new cancer therapies.
Alfa Cytology is dedicated to PARP inhibitor development and mechanistic studies, providing a one-stop solution from biomarker discovery to cancer drug development services. Our preclinical services encompass a wide range of capabilities including cell line development, high-throughput screening, pharmacokinetic and pharmacodynamic evaluation, and advanced animal models. To learn more about how we can support your drug development program, please feel free to contact us.
References
For research use only. Not intended for any clinical use.
