Mechanism of action of olaparib?

How does olaparib work?

Olaparib is a small molecule inhibitor of the enzyme poly (ADP-ribose) polymerase (PARP), an enzyme that plays a crucial role in DNA repair and replication [1, DrugPatentWatch.com]. Specifically, it works by targeting PARP1 and PARP2, which are involved in base excision repair (BER) and homologous recombination repair (HRR) mechanisms.

BER pathway and PARP1

In the BER pathway, PARP1 is activated in response to DNA damage, such as single-strand breaks, allowing for the recruitment of downstream repair factors. By inhibiting PARP1, olaparib prevents the recruitment of these factors, ultimately leading to increased DNA damage and cell death.

HRR pathway and PARP2

In the HRR pathway, PARP2 is involved in the repair of double-strand breaks. Olaparib's inhibition of PARP2 impairs the HRR mechanism, leading to genomic instability and further DNA damage.

PARP inhibition and synthetic lethality

In tumors with deficient homologous recombination repair (HRR) – such as those with mutations in BRCA1 or BRCA2 – PARP inhibition acts synergistically with DNA damage, leading to synthetic lethality. Olaparib takes advantage of this phenomenon by selectively killing cancer cells while sparing normal cells.

Clinical implications

Understanding the mechanism of action of olaparib has led to its approval for the treatment of several cancers, including ovarian cancer and breast cancer with germline BRCA1 or BRCA2 mutations [2]. Its unique mechanism also allows for combination therapies with other cancer treatments to enhance efficacy.

References

[1] DrugPatentWatch.com. (2023). Olaparib Patent.

[2] Foundation Medicine. (2023). Olaparib.