Given the importance of ubiquitin-specific protease 7 (USP7) in oncogenic pathways, identification of USP7 inhibitors has attracted considerable interest. Despite substantial efforts, however, the development of validated deubiquitinase (DUB) inhibitors that exhibit drug-like properties and a well-defined mechanism of action has proven particularly challenging. In this article, we describe the identification, optimization and detailed characterization of highly potent (IC < 10 nM), selective USP7 inhibitors together with their less active, enantiomeric counterparts. We also disclose, for the first time, co-crystal structures of a human DUB enzyme complexed with small-molecule inhibitors, which reveal a previously undisclosed allosteric binding site. Finally, we report the identification of cancer cell lines hypersensitive to USP7 inhibition (EC < 30 nM) and demonstrate equal or superior activity in these cell models compared to clinically relevant MDM2 antagonists. Overall, these findings demonstrate the tractability and druggability of DUBs, and provide important tools for additional target validation studies.
Ubiquitin specific protease 7 (USP7, HAUSP) has become an attractive target in drug discovery due to the role it plays in modulating Mdm2 levels and consequently p53. Increasing interest in USP7 is emerging due to its potential involvement in oncogenic pathways as well as possible roles in both metabolic and immune disorders in addition to viral infections. Potent, novel, and selective inhibitors of USP7 have been developed using both rational and structure-guided design enabled by high-resolution cocrystallography. Initial hits were identified via fragment-based screening, scaffold-hopping, and hybridization exercises. Two distinct subseries are described along with associated structure-activity relationship trends, as are initial efforts aimed at developing compounds suitable for experiments. Overall, these discoveries will enable further research into the wider biological role of USP7.
Despite the efficacy of mammography and the widespread promotion of screening programmes, a significant number of eligible women still do not attend for regular breast screening. An integrative review methodology was considered the most appropriate means to critically analyse the available literature pertaining to factors which influence participation in breast cancer screening. From the extensive literature search, 12 selected core research papers met the inclusion criteria and were incorporated in the literature review. Four themes emerged from the literature which impact on participation in mammography screening: psychological and practical issues, ethnicity issues, influence of socioeconomic status and issues related to screening programmes. The recent Independent Review Panel on Breast Cancer Screening endorsed the importance of access to information which clearly communicates the harms and benefits of breast screening to enable women to make informed decisions about their health. The recommendations from the panel and others have been included in this review.
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 < 5.0 nM) and reversible USP19 inhibitors have been identified. Further profiling has 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 both cancer and muscle cells with EC50 values < 30 nM. We will describe the development of lead molecules with drug-like properties which have allowed us to establish pharmacological target validation by demonstrating efficacy in a muscle wasting model in vivo. Recent developments in the programme leading to orally available USP19 inhibitors will also be presented. This work further exemplifies the tractability of the DUB target family and reports the discovery and detailed profiling of first-in-class inhibitors of USP19. These findings support the rationale to target USP19 for debilitating muscle wasting disorders associated with various conditions such as cancer, as well as for potentially other therapeutic indications, particularly those associated with aberrant protein quality control. Citation Format: Xavier Jacq, Gerald Gavory, Colin O'Dowd, 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.
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