Poly(ADP-Ribose) Polymerase-1 Inhibitors Drug Discovery, Design, and Development as Anticancer Agents from Past to Present: A Mini-Review

Abstract

Cancer treatments are known for their life-threatening toxicities attributed to their low selectivity; hence, new therapeutic approaches are being developed as alternatives. Among those approaches is the DNA repair mechanism, where its inhibition results selectively in the death of cancerous cells. Poly(ADP-Ribose) Polymerase (PARP) is one of the enzymes involved in the repair of damaged DNA. The inhibition of PARP shows to be a promising approach for effective targeted treatment of cancer, especially in tumours with pre-existing Homologous-Repair (HR) defects (i.e., BRCA). Nicotinamide, which is one of the PARP catalytic products, was the first identified PARP inhibitor (PARPi). The first FDA-approved PARPi was Olaparib in 2014 for the treatment of BRCA mutated advanced ovarian cancer. Several clinical trials have been conducted to further improve PARPi. However, there are some concerns related to drug resistance, PARPi sensitive-tumour identification, and toxic accumulation of PARPi. This report will review the uses of PARPi, drug design and development of PARPi from past to present, current issues, and prospective plans.

Recent Discovery of PARP7 Inhibitors as Anticancer Agents

“…The table below shows PARP7 enzyme inhibitory activity of exemplary compounds tested and the reported IC 50 . The pharmacokinetic properties were evaluated for selected compounds in mice following a single 100 mg/kg dose of 51 (121, F%), 84A (106, F%), and 85A (301, F%). …”

Design, Synthesis, and Evaluation of [18F]BIBD-300 as a Positron Emission Tomography Tracer for Poly(ADP-Ribose) Polymerase-1

“…If PARP is inactivated, these cancer cells are unable to repair damaged DNA and may even die, while normal cells can still tolerate it. ,− PARP-1 is the most important member of the PARP family and plays more than 90% of the functions of the PARP family in cells . Therefore, PARP-1-targeting inhibitors, such as olaparib, rucaparib, niraparib, and talazoparib, have been developed and approved as therapeutic drugs for breast cancer, ovarian cancer, pancreatic cancer, and other tumors. − …”