Poly(ADP-ribose)polymerases (PARPs) are a super-family of 18 enzymes that share close sequence homology, and play crucial roles in biological processes ranging from maintenance of genomic stability to apoptosis. These functions depend on PARP catalysing the formation of poly(ADP-ribose) from nicotinamide adenine dinucleotide (NAD+). Owing to its role in DNA single strand break repair via the base-excision repair pathway, PARP1 is an interesting cancer therapeutic target. Tumours with deficiencies in the breast cancer susceptibility gene (BRCA) are particularly susceptible to PARP inhibitors; due to a synthetic lethality arising through defective homologous recombination DNA repair. Rucaparib and BMN-673 are prominent examples of PARP1 inhibitors in clinical trials, although neither fully discriminate between PARP isoforms. Multiple protein targets are usually disadvantageous for therapeutic agents, but evaluating multi-targeted versus target-selective inhibitors is extremely challenging due to this lack of selectivity. In order to develop PARP isoform-specific inhibitors, we have employed the benzimidazole-4- carboxamide broad spectrum PARP inhibitors NU1076 (1) and NU1085 (2) as templates to develop a focussed library of compounds functionalised at the 5-(R1)and 6-(R2) positions. These chemical probes were designed to exploit a unique selectivity pocket, engineered by site-directed mutagenesis, within the NAD-binding domain of PARP1. The synthesis and biological evaluation of benzimidazole-4-carboxamides against wild-type and mutant PARP1 enzymes, in tandem with structural biology studies, will guide the design of further inhibitors, with the objective of identifying potent and selective PARP inhibitors.

Synthesis and biological evaluation of potential isoform-selective benzimidazole-4-carboxamide inhibitors of poly(ADP-ribose)polymerases

249th National Meeting (2015)

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