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Target Overview
Poly [ADP-ribose] polymerases (PARPs) are a group of proteins known to be involved in the repair of single-strand breaks in DNA.1
A healthy cell’s DNA undergoes damage every day, with approximately 10,000 spontaneous single-strand breaks that require repair.1
Inhibition of PARP1 with palacaparib (AZD9574) leads to the trapping of PARP1 bound to DNA single-strand breaks, stalling of replication forks, their collapse and the generation of DNA double-strand breaks and cancer cell death. In tumor cells that already have compromised DNA repair mechanisms (such as loss of BRCA1 or BRCA2 function, affecting double-strand break repair), inhibition of PARP1 leads to excessive accumulation of DNA damage and may cause death of the cell.1,2
Compound Overview
Palacaparib (AZD9574) is an investigational, next generation CNS penetrant PARP inhibitor. It is designed to selectively inhibit and trap PARP1 as well as specifically penetrate the blood-brain barrier.3,4
Mechanism of Action
References
1. Underhill C, Toulmonde M, Bonnefoi H. Ann Oncol. 2011;22(2):268-279. 2. Yelamos J, Farres J, Llacuna L, et al. Am J Cancer Res. 2011;1(3):328-346. 3. Johannes JW, Balazs AY, Barratt D, et al. Journal of Medicinal Chemistry. 2024;67(24):21717-1728. 4. Staniszewska AD, Pilger D, Gill SJ, et al. Clinical Cancer Research. 2024;30(7):1338-1351.
Target Overview
Poly [ADP-ribose] polymerases (PARPs) are a group of proteins known to be involved in the repair of single-strand breaks in DNA.1
A healthy cell’s DNA undergoes damage every day, with approximately 10,000 spontaneous single-strand breaks that require repair.1
Inhibition of PARP1 with palacaparib (AZD9574) leads to the trapping of PARP1 bound to DNA single-strand breaks, stalling of replication forks, their collapse and the generation of DNA double-strand breaks and cancer cell death. In tumor cells that already have compromised DNA repair mechanisms (such as loss of BRCA1 or BRCA2 function, affecting double-strand break repair), inhibition of PARP1 leads to excessive accumulation of DNA damage and may cause death of the cell.1,2
Compound Overview
Palacaparib (AZD9574) is an investigational, next generation CNS penetrant PARP inhibitor. It is designed to selectively inhibit and trap PARP1 as well as specifically penetrate the blood-brain barrier.3,4
Mechanism of Action
References
1. Underhill C, Toulmonde M, Bonnefoi H. Ann Oncol. 2011;22(2):268-279. 2. Yelamos J, Farres J, Llacuna L, et al. Am J Cancer Res. 2011;1(3):328-346. 3. Johannes JW, Balazs AY, Barratt D, et al. Journal of Medicinal Chemistry. 2024;67(24):21717-1728. 4. Staniszewska AD, Pilger D, Gill SJ, et al. Clinical Cancer Research. 2024;30(7):1338-1351.
Clinical trial information
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CERTIS1 trial overview
Abbreviations
BRCA 1/2
breast cancer susceptibility gene 1/2
CNS
central nervous system
DNA
deoxyribonucleic acid
PARP
poly (ADP-ribose) polymerase
PARP1
poly (ADP-ribose) polymerase 1