Medicinal chemistry approaches of poly ADP-Ribose polymerase 1 (PARP1) inhibitors as anticancer agents - A recent update

Abstract

Poly (ADP-ribose) Polymerase1 (PARP1) is a member of 17 membered PARP family having diversified biological functions such as synthetic lethality, DNA repair, apoptosis, necrosis, histone binding etc. It is primarily a chromatin-bound nuclear enzyme that gets activated by DNA damage. It binds to DNA signal- and double-strand breaks, does parylation of target proteins (using NAD⁺ as a substrate) like histones and other DNA repair proteins and modifies them as a part of DNA repair mechanism. Inhibition of PARP1 prevents the DNA repair and leads to cell death. Clinically, PARP1 Inhibitors have shown their potential in treating BRCAm breast and ovarian cancers and trials are going on for the treatment of other solid tumors like pancreatic, prostate, colorectal etc. as a single agent or in combination. There are currently three FDA approved PARP1 inhibitors namely Olaparib, Rucaparib and Niraparib in the market while Veliparib and Talazoparib are in the late stage of clinical development. All these molecules are nonselective PARP1 inhibitors with concurrent inhibition of PARP2 with similar potency. In addition, resistance to marketed PARP1 inhibitors has been reported. Overall, looking at the success rate of PARP1 inhibitors into various solid tumors, there is an urge of a novel and selective PARP1 inhibitors. This review provides an update on various newer heterocyclic PARP1 inhibitors reported in last three years along with their structural design strategies. We classified them into two main chemical classes; NAD analogues and non-NAD analogues and discussed the medicinal chemistry approaches of each class. To understand the structural features required for in-silico designing of next-generation PARP1 inhibitors, we also reported the crucial amino acid interactions of these inhibitors at the target site. Thus, present review provides the insight on recent development on new lead structures as PARP1 inhibitors, their SAR, an overview of in-vitro and in-vivo screening methods, current challenges and opinion on future designing of more selective and safe PARP1 inhibitors.

Keywords: ADP ribosylation; BRCA; Cancer; DNA repair; Histone modification; NAD analogues; Non-NAD analogues; PARP1 inhibitors; Synthetic lethality.