Design and Synthesis of Selective Inhibitors for Poly(ADP-ribose) polymerase Member 14 (PARP14)

Prostate Cancer (PCa) is the second most commonly diagnosed cancer for men in western countries, and it is one of the most deadly cancers globally (1). Late stage PCa is highly aggressive and has the potential to spread throughout
the body, limiting the treatment options. The poly (ADP-Ribose) polymerase, or PARP, is a superfamily of enzymes which are found in eukaryotic cells and modify histones and other nuclear proteins that are responsible for the
survival of damaged, proliferating cells via poly(ADP-ribosyl)ation (2). PARP14 was found to be moderately overexpressed in PCa and some other cancers, and has been found to promote the Warburg effect and DNA repair mechanisms, aiding cell survival. Inhibition of PARP14 could potentially increase the efficacy of current oncotherapies (3).
Nine compounds were designed to potentially inhibit PARP14. The compounds were designed and computationally analysed using PyRx and Chimera. Key binding residues in PARP14 include His1601, Tyr1620, Tyr1633 and Tyr1640
(3SMI.pdb). All nine compounds displayed favourable binding affinities and key interactions that may help with selectively targeting PARP14 over the other PARP superfamily enzymes. The nine compounds were synthesised and characterised prior to PARP14 enzyme inhibition studies.