A review on recent PARP inhibitor advancements in cancer therapy.

Abstract

Poly [ADP-ribose] polymerase-1 [PARP-1] is a chromatin-bound nuclear enzyme that gets activated by DNA damage, it facilitates DNA repair by binding to DNA breaks and attracting DNA repair proteins to the site of damage. Increased PARP-1 expression is observed in melanomas, breast cancer, lung cancer, and other neoplastic diseases. PARP-1 interacts directly, indirectly with various oncogenic proteins and regulates several transcription factors thereby modulating carcinogenesis. There is a lot of pre-clinical and clinical data supporting the use of PARP-1 inhibitors [PARP-1i] in cancers that express homologous recombination deficiencies like mutations within BRCA-1/2 genes. Therapeutic inhibition of PARP-1 is therefore perceived as a promising anticancer strategy and numerous PARP-1i are currently under development and clinical evaluation. Currently, there are 4 FDA-approved PARP-1i in the market, while few are in the last stage of clinical development. All the molecules are non-selective PARP-1i. While giving promising results, PARP-1i have their own disadvantages, like safety problems, resistance, etc. Looking at the success rate of PARP-1i in various solid tumours, there is an urge for novel and selective PARP-1i. In this review, we discuss various aspects related to PARP-1i like recent developments, overcoming the resistance, and selectivity criteria of new molecules for potential PARP-1i.