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Cancer cachexia is a metabolic wasting syndrome characterized by weight loss, anorexia and anemia as a result of tumor burden, and affects up to 80% of advanced cancer patients #1. Cachexia is particularly prevalent in pancreatic, lung, colorectal and gastro-intestinal cancers and can lead to reduced tolerance and responsiveness to chemotherapy, increased treatment-related toxicity and morbidity, and poor overall quality of life. There are currently no approved therapies for cancer cachexia. The development and maintenance of muscle tissue is dependent on the balance between protein synthesis and protein degradation, controlled through various anabolic and catabolic signaling pathways. Dysregulation of these pathways can result in muscle atrophy, which arises in many chronic illnesses. The ubiquitin proteasome system (UPS) has a central role in regulating skeletal muscle physiology. Previous work utilizing USP19 knock out mouse models has demonstrated that USP19 plays an important role in muscle wasting and can protect against denervation-induced muscle atrophy #2. We have previously demonstrated that inhibition of USP19 enzymatic activity spares the muscle wasting observed in limb-casted and denervated mouse models of muscle wasting. Here, we report the discovery of a novel, highly potent and selective inhibitor of USP19 (ADC-846) and demonstrate its utility in a cancer-induced muscle atrophy model in vivo. Pharmacological inhibition of USP19 by ADC-846 increased lean muscle and fat mass following oral dosing in a Lewis Lung Carcinoma-induced cachexia model and reduced the cachexic index by >60% compared to controls. This data, in combination with our previous work detailing the effect of USP19 inhibition on muscle force and function, provides a much-needed novel pharmacological strategy for therapeutic intervention in muscle wasting conditions. Citation Format: Natalie Page, Vignesh Karthikaisamy, Darren O'Hara, Aaron N. Cranston, Colin R. O'Dowd, Xavier Jacq, Richard Wilkinson, Stephanie Burton, Hayley Gibson, Joana Costa, Daniel Longley, Matthew Helm, Chris McGivern, Steven Shepherd, Christina Bell, Peter Hewitt, Mary McFarland, Hugues Miel, Steven Whitehead, Lauren Proctor, Shane J. Rountree, Mark Wappett, Mauricio Berriel Diaz, Stephan Herzig, Timothy Harrison. A novel first-in-class USP19 inhibitor for the treatment of cancer-induced muscle atrophy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB022.

What is the relationship between language and the world it supposedly depicts? Is it possible to establish a straightforward correspondence between language and language independent facts, or does language in some way shape the way in which we see things? As natural languages seem to each have their own specific characteristics, as their vocabularies and grammars differ in significant respects, it seems impossible to establish a sphere of universally shared meaning. Meaning would seem to be embedded in the particular languages through which it is conveyed, but if that were the case, how would it ever be possible to understand another language or to translate from one language into another?Placing too much emphasis on the differences between languages would make understanding such differences impossible. Understanding is necessarily based on mutually shared concepts. On the other hand, if understanding is based on generally shared concepts, how is it possible to understand and convey the individual charact...

[Image: see text] 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 in vivo experiments. Overall, these discoveries will enable further research into the wider biological role of USP7.

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.

Introduction: Young-onset dementia affects about 1 in 1500 people aged under 65 years in the United Kingdom (UK). It is associated with loss of employment, independence and an increase in psychological distress. This project set out to identify the benefits of a 2 hours per week structured activity programme of gardening for people with young-onset dementia. Method: A mixed methods (qualitative and quantitative) study of therapeutic gardening for people with young-onset dementia, measuring outcomes for both participants with young-onset dementia and their carers, was used. Twelve participants were recruited from a county-wide mental health service for older adults, based on onset of dementia being before the age of 65 years (range 43–65 years). Of these, two participants dropped out and one died during the project. Measures included the Mini Mental State Examination (MMSE), Bradford Well-Being Profile, Large Allen Cognitive Level Screen (LACLS) and Pool Activity Level (PAL). Findings: Over a 1-year period the carers of the people with young-onset dementia found that the project had given participants a renewed sense of purpose and increased well-being, despite cognitive functioning continuing to decline during this period. Conclusion: This study suggests that a meaningful guided activity programme can maintain or improve well-being in the presence of cognitive deterioration.

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. As a result of their increasing implications in the etiology of numerous pathological conditions including cancer and immuno-oncology, DUBs have emerged as an attractive and promising target class for the development of first-in-class medicines with high therapeutic impact. However, despite 15 years of intense research DUBs have proven largely refractory to drug discovery efforts. Herein, we further describe the application of UbiPlex™, our purpose-built drug discovery platform for the identification and development of DUB inhibitors. In particular, we will highlight the versatility and robustness of UbiPlex™ by reporting the outcome of our focussed library screening campaign on multiple DUBs in parallel and by describing the de novo hit ID, orthogonal validation and hit optimization activities on two USPs of relevance to cancer. Multiple series of novel, highly potent (e.g. IC50 < 20 nM) and non-covalent inhibitors have been developed. Excellent selectivity profiles against a large panel of DUBs and other non-related enzymes (e.g. proteases) will be described. Further profiling indicated that these inhibitors are cell-permeable and exhibit potent target engagement in cells (e.g. EC50 < 30 nM). Finally, we will describe our progress towards the development of lead molecules with drug-like properties with the aim of rapidly establishing proof-of-concept studies in vivo. In summary, this work further exemplifies the broad tractability and druggability of the DUBome and reports the discovery and profiling of novel highly potent and selective inhibitors beyond USP7. These molecules may provide opportunities for the development of new therapeutics for cancer and associated disorders. Citation Format: Gerald Gavory, Colin O'Dowd, Oliver Barker, Christina Bell, Frank Burkamp, Stephanie Burton, Eamon Cassidy, Joana Costa, Anthony Dossang, Matt Helm, Ashling Henderson, Peter Hewitt, Caroline Hughes, Mary McFarland, Hugues Miel, Natalie Page, Lauren Proctor, Shane Rountree, Ewelina Rozycka, Steven Shepherd, Adam Treder, Mark Wappett, Steven Whitehead, Tim Harrison. Accessing the cancer DUBome with UbiPlex: A bespoke drug discovery platform for deubiquitinase enzymes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1935.

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

A unique new method is described showing the use of microfiltration and ultrafiltration membranes in conjunction with gel permeation in 96 well plates. Using this technique it is possible to clean up DNA sequencing reactions to a level of template DNA purity that makes high DNA loading onto capillary electrophoresis (CE) sequencers possible. Loadings as high as 10, 000 ng allow sequencing on CE to be equal in performance to gel slab electrophoresis. This technique replaces alcohol precipitation for sequencing reaction cleanup with an easily automated process taking 1/6 the time.

The identification of a novel fused triazolo-pyrrolopyridine scaffold, optimized derivatives of which display nanomolar inhibition of Janus kinase 1, is described. Prototypical example 3 demonstrated lower cell potency shift, better permeability in cells and higher oral exposure in rat than the corresponding, previously reported, imidazo-pyrrolopyridine analogue 2. Examples 6, 7 and 18 were subsequently identified from an optimization campaign and demonstrated modest selectivity over JAK2, moderate to good oral bioavailability in rat with overall pharmacokinetic profiles comparable to that reported for an approved pan-JAK inhibitor (tofacitinib).

Herein we report the discovery of the C-2 methyl substituted imidazopyrrolopyridine series and its optimization to provide potent and orally bioavailable JAK1 inhibitors with selectivity over JAK2. The C-2 methyl substituted inhibitor 4 exhibited not only improved JAK1 potency relative to unsubstituted compound 3 but also notable JAK1 vs JAK2 selectivity (20-fold and >33-fold in biochemical and cell-based assays, respectively). Features of the X-ray structures of 4 in complex with both JAK1 and JAK2 are delineated. Efforts to improve the in vitro and in vivo ADME properties of 4 while maintaining JAK1 selectivity are described, culminating in the discovery of a highly optimized and balanced inhibitor (20). Details of the biological characterization of 20 are disclosed including JAK1 vs JAK2 selectivity levels, preclinical in vivo PK profiles, performance in an in vivo JAK1-mediated PK/PD model, and attributes of an X-ray structure in complex with JAK1.

Pain is a personal, subjective experience. In the postoperative period, pain may be influenced by patient, pharmacological and environmental factors. In surgery the aim is to reduce pain in this period by educating patients and using adequate analgesia. The aim of the present study was to assess the effect of perceived wound size on pain, as indicated by wound dressing, in the immediate postoperative period.Patients undergoing appendicectomy were randomized into a group having a dressing the same size (SSD) as the surgical wound or double the size (DSD) of the wound. Patients' pain perception and analgesic requirements were then recorded and analysed to compare the two groups.Both groups had similar results when comparing pain perception. The median total pain score for the SSD and DSD groups at 12 and 24 h postoperatively revealed no statistically significant difference (P0.05).The data do not support the hypothesis that postoperative pain may be altered by perceived wound dressing size. Dressing size does not appear to be a variable that could easily be altered to reduce postoperative pain in surgical patients.