Design and Synthesis of Potential ARTD8 inhibitors towards the treatment of Metastatic Prostate Cancer

Metastatic prostate cancer is currently the third leading cause of cancer related death in Australia, in part due to its increasing prevalence and lack of therapies able to overcome the androgen independent nature of the late stage disease. A potential target could be ADP-ribosyl transferase member 8 (ARTD8, aka. PARP14, CoaSt6, BAL2). Part of the 17-membered family of post-translational modifiers, ARTD8 has gained traction as a chemopreventive target due to the correlation between its expression and the pathogenesis of many metastatic cancers, including prostate (Bachmann et al., 2014). As of yet, there is no clinically available selective ARTD8 inhibitor. Our research explores the design, synthesis and in vitro evaluation of nine ARTD8 inhibitors. Designed as a lengthened nicotinamide mimic with the intention of interacting with both the catalytic and adenine binding subsites of the ARTD8 catalytic domain. The proposed compounds were designed and docked using AutoDock Vina, observing that many of the compounds spanned across both subsites of the domain. These nine novel compounds were synthesised using reductive amination. Preliminary assay results of compounds 7, 8 and 9 displayed a 55% reduction in ARTD8 activity.