PARP-1 Inhibitor (Poly(ADP-ribose) Polymerase-1 Inhibitor)

### Overview PARP-1 inhibitors are a class of drugs that target poly(ADP-ribose) polymerase 1 (PARP-1), an enzyme involved in DNA repair, particularly the base excision repair (BER) pathway. These inhibitors are used primarily in the treatment of cancers with defective homologous recombination repair (HRR), such as BRCA1/2-mutated ovarian, breast, prostate, and pancreatic cancers.

### Mechanism of Action PARP-1 inhibitors work by trapping PARP on damaged DNA and preventing the repair of single-strand DNA breaks. This leads to the accumulation of DNA damage, which, in HRR-deficient cancer cells, results in synthetic lethality and cell death.

1. PARP Inhibition – Blocks the enzymatic activity of PARP-1. 2. PARP Trapping – Causes PARP-1 to remain bound to DNA, preventing its repair. 3. Synthetic Lethality – In cells with BRCA1/2 mutations, failure to repair DNA leads to double-strand breaks (DSBs), triggering apoptosis.

### Clinical Applications PARP-1 inhibitors are FDA-approved for multiple cancers, including: - Ovarian cancer (especially BRCA-mutated and platinum-sensitive cases) - Breast cancer (HER2-negative, BRCA-mutated) - Prostate cancer (HRR-deficient) - Pancreatic cancer (BRCA-mutated)

### Examples of PARP-1 Inhibitors

### Side Effects Common side effects include: - Fatigue - Nausea and vomiting - Anemia - Thrombocytopenia - Neutropenia - Myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) (rare but serious)

### Future Directions PARP inhibitors are being explored in: - Combination therapies with immune checkpoint inhibitors, chemotherapy, and radiotherapy. - Expanding indications beyond BRCA-mutant cancers. - Targeting PARP resistance mechanisms to enhance efficacy.