Development of tankyrase-directed PROTACs as novel scaffolding inhibitors

The poly(ADP-ribosyl)transferase tankyrase (TNKS, TNKS2) controls a wide range of cancer-relevant cellular processes, including Wnt/catenin signalling, telomere length homeostasis and Hippo signalling1. Hence, tankyrase catalytic inhibitors are being developed as molecular probes and potential therapeutic agents2. All tankyrase inhibitors available to date act as antagonists of NAD+ co-substrate binding. As they block poly(ADP-ribose)-induced ubiquitylation and degradation of tankyrase and its substrates, they typically give rise to strong tankyrase accumulation. Therefore, catalytic inhibitors do not contain, and may even exacerbate, non-catalytic functions of tankyrase that have recently been reported3,4. To circumvent these potential limitations, we are developing compounds that block the interaction between tankyrase and its effector proteins as chemical tools to investigate catalytic vs. non-catalytic functions of tankyrase5. In this project, we propose to optimise effector binding antagonists of tankyrase and evolve the resulting molecules into novel PROTACs6 that engage tankyrase via its effector-binding modules rather than its catalytic domain. Unlike catalytic inhibitors, we predict that such molecules will not trigger the accumulation of tankyrase and may therefore be more suitable for PROTAC development. We envisage that tankyrase-directed PROTACs will help dissect the functions of tankyrase as a key player in numerous processes linked to cancer and other pathologies such as diabetes, neurodegeneration and fibrosis.