Heterocyclic Scaffolds in PARP-1 Inhibition: An Emerging Strategy for Targeted Anticancer Therapy.

INTRODUCTION: Poly (ADP-ribose) polymerase-1 (PARP-1) is a key regulator of DNA repair, genomic stability, and programmed cell death. PARP-1 inhibition induces synthetic lethality in homologous recombination-deficient tumors, particularly those with BRCA mutations. Firstgeneration PARP inhibitors, including Olaparib, Niraparib, Talazoparib, and Rucaparib, have significantly advanced targeted cancer therapy but are limited by toxicity, resistance, and off-target effects. This review aims to highlight the potential of heterocyclic scaffolds for developing selective and improved PARP-1 inhibitors, with emphasis on structure-activity relationships and optimization strategies. METHODS: Published literature, crystallographic studies, and preclinical evaluations were analysed to assess heterocyclic frameworks such as quinazolines, benzimidazoles, oxadiazoles, thiadiazoles, triazoles, and indoles. Design strategies including scaffold hopping, bioisosteric replacement, and hybrid design were evaluated for their impact on potency, selectivity, and pharmacological performance. RESULTS: Heterocyclic scaffolds demonstrated strong binding to the PARP-1 catalytic domain through hydrogen bonding and π-π stacking with key residues (e.g., Gly863 and Tyr907). SAR studies showed that halogenation, methoxy substitution, Schiff bases, and azole linkers enhanced potency, solubility, and pharmacokinetics. Next-generation scaffolds, such as triazolo-pyrazines and benzimidazoles, exhibited improved PARP-1 selectivity over PARP-2, reducing haematological toxicity and improving antiproliferative activity in BRCA-mutated models. DISCUSSION: Rational heterocycle-based design improves selectivity, metabolic stability, and tumor targeting, addressing key limitations of existing PARP inhibitors. CONCLUSION: Heterocyclic scaffolds offer a promising route toward next-generation PARP-1 inhibitors with enhanced efficacy, reduced resistance, and optimized safety, supporting personalized anticancer therapy.