parp-1_inhibitor [Neurosurgery Wiki]

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**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**
| Drug | Brand Name | Indications |
|------|------------|-------------|
| **Olaparib** | Lynparza | Ovarian, breast, prostate, pancreatic cancer |
| **Rucaparib** | Rubraca | Ovarian, prostate cancer |
| **Niraparib** | Zejula | Ovarian cancer |
| **Talazoparib** | Talzenna | Breast cancer |
| **Veliparib** (investigational) | - | Various cancers (clinical trials) |

### **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.