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Experimental and Molecular Therapeutics

Abstract 1181: Discovery and development of novel highly potent and selective inhibitors of USP19 using UbiPlex™

Gerald Gavory, Colin O'Dowd, Ewelina Rozycka, Anthony Dossang, Ashling Henderson, Caroline Hughes, Hugues Miel, Oliver Barker, Joana Costa, Peter Hewitt, Mary McFarland, Lauren Proctor and Tim Harrison
Gerald Gavory
Almac Discovery, Belfast, United Kingdom.
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Colin O'Dowd
Almac Discovery, Belfast, United Kingdom.
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Ewelina Rozycka
Almac Discovery, Belfast, United Kingdom.
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Anthony Dossang
Almac Discovery, Belfast, United Kingdom.
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Ashling Henderson
Almac Discovery, Belfast, United Kingdom.
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Caroline Hughes
Almac Discovery, Belfast, United Kingdom.
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Hugues Miel
Almac Discovery, Belfast, United Kingdom.
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Oliver Barker
Almac Discovery, Belfast, United Kingdom.
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Joana Costa
Almac Discovery, Belfast, United Kingdom.
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Peter Hewitt
Almac Discovery, Belfast, United Kingdom.
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Mary McFarland
Almac Discovery, Belfast, United Kingdom.
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Lauren Proctor
Almac Discovery, Belfast, United Kingdom.
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Tim Harrison
Almac Discovery, Belfast, United Kingdom.
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DOI: 10.1158/1538-7445.AM2017-1181 Published July 2017
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Proceedings: AACR Annual Meeting 2017; April 1-5, 2017; Washington, DC

Abstract

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) are cysteine proteases that catalyse the de-ubiquitination of protein substrates including tumor suppressors and oncogenes, hence regulating their levels and/or function. As a result of their increasing implications in the etiology of numerous pathological conditions including cancer, DUBs are emerging as an attractive and promising target class for the development of 1st in class medicines with high therapeutic impact. However, despite 15 years of intense research DUBs have proved largely refractory to drug discovery efforts.

Herein, we further describe the application of Ubi-Plex™, our drug discovery platform for the identification and optimisation of DUB inhibitors. In particular, we will highlight the versatility and robustness of Ubi-Plex™ by describing the outcome of our focussed library screening, hit identification, hit validation and elaboration activities on USP19.

A series of novel, highly potent (e.g. IC50 < 10 nM) and reversible USP19 inhibitors have been identified. Further profiling has also demonstrated excellent selectivity against a large panel of DUBs and other non-related enzymes (e.g. kinases, proteases). These inhibitors are cell-permeable and exhibit potent target engagement in cells with EC50 values < 30 nM. Finally, we will describe our progress towards the development of lead molecules with drug-like properties with the aim to rapidly establish in vivo proof-of-concept studies.

In summary, this work further exemplifies the tractability of the DUB target family and reports the discovery and detailed profiling of the first highly potent and selective inhibitors of USP19. These molecules may provide opportunities for the development of new anticancer therapeutics as well as for the treatment of muscle wasting disorders including cachexia.

Citation Format: Gerald Gavory, Colin O'Dowd, Ewelina Rozycka, Anthony Dossang, Ashling Henderson, Caroline Hughes, Hugues Miel, Oliver Barker, Joana Costa, Peter Hewitt, Mary McFarland, Lauren Proctor, Tim Harrison. Discovery and development of novel highly potent and selective inhibitors of USP19 using UbiPlex™ [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1181. doi:10.1158/1538-7445.AM2017-1181

  • ©2017 American Association for Cancer Research.
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Cancer Research: 77 (13 Supplement)
July 2017
Volume 77, Issue 13 Supplement
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Abstract 1181: Discovery and development of novel highly potent and selective inhibitors of USP19 using UbiPlex™
Gerald Gavory, Colin O'Dowd, Ewelina Rozycka, Anthony Dossang, Ashling Henderson, Caroline Hughes, Hugues Miel, Oliver Barker, Joana Costa, Peter Hewitt, Mary McFarland, Lauren Proctor and Tim Harrison
Cancer Res July 1 2017 (77) (13 Supplement) 1181; DOI: 10.1158/1538-7445.AM2017-1181

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Abstract 1181: Discovery and development of novel highly potent and selective inhibitors of USP19 using UbiPlex™
Gerald Gavory, Colin O'Dowd, Ewelina Rozycka, Anthony Dossang, Ashling Henderson, Caroline Hughes, Hugues Miel, Oliver Barker, Joana Costa, Peter Hewitt, Mary McFarland, Lauren Proctor and Tim Harrison
Cancer Res July 1 2017 (77) (13 Supplement) 1181; DOI: 10.1158/1538-7445.AM2017-1181
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Cancer Research Online ISSN: 1538-7445
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