What is the mechanism of Pamiparib?

Pamiparib is a potent and selective inhibitor of poly (ADP-ribose) polymerase (PARP), an enzyme family involved in various cellular processes, including DNA repair, genomic stability, and programmed cell death. The mechanism of Pamiparib centers around its ability to inhibit PARP enzymes, thus interfering with the DNA damage response and enhancing the cytotoxic effects of DNA-damaging agents.

At the core of Pamiparib's action is its inhibition of PARP-1 and PARP-2 enzymes, which play critical roles in the repair of single-strand DNA breaks through the base excision repair (BER) pathway. When Pamiparib binds to the catalytic domain of PARP enzymes, it prevents the transfer of ADP-ribose units from NAD+ to target proteins, a process essential for the recruitment and assembly of DNA repair complexes at the site of damage. By inhibiting PARP activity, Pamiparib effectively hampers the repair of single-strand breaks, resulting in the accumulation of DNA damage.

This accumulated DNA damage can lead to the formation of double-strand breaks, particularly during DNA replication. In cells with functional homologous recombination (HR) repair mechanisms, these double-strand breaks can be accurately repaired. However, in cells deficient in HR repair, such as those with BRCA1 or BRCA2 mutations, the inability to correctly repair these breaks can lead to cell death. This concept forms the basis of synthetic lethality, where the combination of PARP inhibition and HR deficiency leads to selective cytotoxicity in cancer cells while sparing normal cells.

Beyond its role in inhibiting DNA repair, Pamiparib also induces PARP trapping, a phenomenon where the PARP-DNA complex becomes stabilized at the site of DNA damage. These trapped PARP-DNA complexes are particularly toxic as they can obstruct replication forks and transcription processes, further contributing to genomic instability and cell death.

Pamiparib has shown promise in preclinical and clinical studies, demonstrating efficacy in treating various cancers, including ovarian, breast, and prostate cancers, especially those with BRCA mutations or other HR deficiencies. Its ability to potentiate the effects of chemotherapy and radiation therapy, by preventing the repair of therapy-induced DNA damage, highlights its potential as a valuable adjunct in cancer treatment regimens.

In summary, the mechanism of Pamiparib involves inhibiting PARP enzymes, preventing the repair of single-strand DNA breaks, inducing the accumulation of DNA damage, and promoting cell death in HR-deficient cancer cells. This targeted approach leverages the concept of synthetic lethality to selectively target tumor cells while minimizing damage to normal tissues. As research continues, Pamiparib holds promise for improving outcomes in patients with specific genetic profiles and enhancing the efficacy of existing cancer therapies.