Design and Synthesis of Novel NON-NAD+ Analogues As Poly(ADP-RIBOSE) Polymerase 1 (PARP1) Inhibitors: Part-2

Abstract

Poly (ADP-Ribose) Polymerase1 (PARP1) is an abundant and ubiquitous nuclear enzyme. When active, it captures NAD+ to assemble long and branching polymers of Poly(ADP-ribose), modifying itself, as well as surrounding proteins. Although DNA repair is commonly accepted as its main function, recent findings indicate that PARP1 also participates in numerous nuclear processes, including regulation of chromatin and gene expression, ribosome biogenesis, nuclear traffic, and epigenetic bookmarking. The majority of currently available PARP1 inhibitors, namely Olaparib, Rucaparib, Niraparib and Talazoparib were designed as NAD+ competitors due to presence of nicotinamide pharmacophore. As NAD+ is utilized by many enzymes other than PARP1, it results in a trade-off trap between their specificity and efficacy. To circumvent this problem, there is a need to develop a new strategy to target PARP1 and provide a highly specific route of its activation. The other overlooked routes of PARP 1 activation are by targeting histone H4 and DNA dependent pathways. Thomas C. et. al. in 2016, discovered new PARP1 inhibitors using a screen based on PARP1 enzymatic activation via histone H4 and found that a few moieties were structurally unrelated to NAD+, out of which the most potent compound obtained from the screen, 5F02, more potently inhibited PARP1 than the marketed drug Olaparib in various breast, prostate and kidney cancer cell lines. The authors also presented a few moieties which could be potential non-NAD+ PARP1 inhibitors. We designed novel non-NAD+ PARP1 inhibitors by selecting thiadiazole containing moiety and prepared a 5F02 like pharmacophore containing molecule and incorporated thiadiazole hit obtained from HTS into it. The designed thiadiazole derivatives were subjected to protein-protein docking to confirm whether the designed molecules could inhibit PARP1 activation by a H4 mediated route. The difference observed in interacting residues of H4 docked in the crystal structure of PARP1 in presence and absence of ligand, showed that in presence of a ligand, H4 does not bind to its original site of interaction, i.e. histone gets inhibited in presence of our designed ligand. Least binding energy having molecules were then synthesized. In vitro cytotoxicity studies are yet to be performed.