Abstract LB-087: Discovery and development of first-in-class orally bioavailable USP19 inhibitors

Over the past decade, protein ubiquitination has emerged as an important post-translational modification with regulatory functions in all important cellular processes. Deubiquitinating enzymes (DUBs) including ubiquitin specific proteases (USPs) catalyse the de-ubiquitination of protein substrates, hence regulating their levels and/or function. As a result of their increasing implications in the aetiology of numerous pathological conditions including cancer, neurodegeneration and metabolic disorders, DUBs represent an attractive and promising target class for the development of innovative medicines with high therapeutic impact. However, despite 15 years of research DUBs have proved largely refractory to drug discovery efforts. As a result of genetic and other validation studies, USP19 has recently emerged as a potentially important target in muscular atrophy associated with various conditions including cancer, as well as in other disorders involving aberrant protein quality control. Herein, we describe the application of our Ubi-Plex™ drug discovery platform to the identification and optimisation of first in class USP19 inhibitors. Several series of novel, highly potent (e.g. IC50 Citation Format: Xavier Jacq, Gerald Gavory, Colin O9Dowd, Aaron Cranston, Oliver Baker, Christina Bell, Stephanie Burton, Eamon Cassidy, Joana Costa, Ashling Henderson, Matthew Helm, Peter Hewitt, Caroline Hughes, Mary McFarland, Hugues Miel, Lauren Proctor, Shane Roundtree, Rachel Church, Ewelina Rozycka, Mark Wappett, Steven Whitehead, Tim Harrison, Nathalie Bedard, Simon S. Wing. Discovery and development of first-in-class orally bioavailable USP19 inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-087.