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19 results on '"Walsh, Jarrod"'

3. Nuisance compounds in cellular assays

Author

Dahlin, Jayme L., Auld, Douglas S., Rothenaigner, Ina, Haney, Steve, Sexton, Jonathan Z., Nissink, J. Willem M., Walsh, Jarrod, Lee, Jonathan A., Strelow, John M., Willard, Francis S., Ferrins, Lori, Baell, Jonathan B., Walters, Michael A., Hua, Bruce K., Hadian, Kamyar, and Wagner, Bridget K.

Published
2021
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4. Discovery, Optimization, and Biological Evaluation of Arylpyridones as Cbl-b Inhibitors

Author

Mfuh, Adelphe M., primary, Boerth, Jeffrey A., additional, Bommakanti, Gayathri, additional, Chan, Christina, additional, Chinn, Alex J., additional, Code, Erin, additional, Fricke, Patrick J., additional, Giblin, Kathryn A., additional, Gohlke, Andrea, additional, Hansel, Catherine, additional, Hariparsad, Niresh, additional, Hughes, Samantha J., additional, Jin, Meizhong, additional, Kantae, Vasudev, additional, Kavanagh, Stefan L., additional, Lamb, Michelle L., additional, Lane, Jordan, additional, Moore, Rachel, additional, Puri, Taranee, additional, Quinn, Taylor R., additional, Reddy, Iswarya, additional, Robb, Graeme R., additional, Robbins, Kevin J., additional, Gancedo Rodrigo, Miguel, additional, Schimpl, Marianne, additional, Singh, Baljinder, additional, Singh, Meha, additional, Tang, Haoran, additional, Thomson, Clare, additional, Walsh, Jarrod J., additional, Ware, Jamie, additional, Watson, Iain D. G., additional, Ye, Min-Wei, additional, Wrigley, Gail L., additional, Zhang, Andrew X., additional, Zhang, Yun, additional, and Grimster, Neil P., additional

Published
2024
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5. A High-Throughput Screening Triage Workflow to Authenticate a Novel Series of PFKFB3 Inhibitors

Author

St-Gallay, Stephen A., Bennett, Neil, Critchlow, Susan E., Curtis, Nicola, Davies, Gareth, Debreczeni, Judit, Evans, Nicola, Hardern, Ian, Holdgate, Geoff, Jones, Neil P., Leach, Lindsey, Maman, Sarita, McLoughlin, Sheila, Preston, Marian, Rigoreau, Laurent, Thomas, Andrew, Turnbull, Andrew P., Walker, Graeme, Walsh, Jarrod, Ward, Richard A., Wheatley, Ed, and Winter-Holt, Jon

Published
2018
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6. Development of a Series of Pyrrolopyridone MAT2A Inhibitors

Author

Atkinson, Stephen J., Bagal, Sharan K., Argyrou, Argyrides, Askin, Sean, Cheung, Tony, Chiarparin, Elisabetta, Coen, Muireann, Collie, Iain T., Dale, Ian L., De Fusco, Claudia, Dillman, Keith, Evans, Laura, Feron, Lyman J., Foster, Alison J., Grondine, Michael, Kantae, Vasudev, Lamont, Gillian M., Lamont, Scott, Lynch, James T., Nilsson Lill, Sten, Robb, Graeme R., Saeh, Jamal, Schimpl, Marianne, Scott, James S., Smith, James, Srinivasan, Bharath, Tentarelli, Sharon, Vazquez-Chantada, Mercedes, Wagner, David, Walsh, Jarrod J., Watson, David, and Williamson, Beth

Abstract

The optimization of an allosteric fragment, discovered by differential scanning fluorimetry, to an in vivo MAT2a tool inhibitor is discussed. The structure-based drug discovery approach, aided by relative binding free energy calculations, resulted in AZ’9567 (21), a potent inhibitor in vitro with excellent preclinical pharmacokinetic properties. This tool showed a selective antiproliferative effect on methylthioadenosine phosphorylase (MTAP) KO cells, both in vitro and in vivo, providing further evidence to support the utility of MAT2a inhibitors as potential anticancer therapies for MTAP-deficient tumors.

Published
2024
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10. Identification of Compounds That Interfere with High-Throughput Screening Assay Technologies

Author

David, Laurianne, Walsh, Jarrod, Sturm, Noé, Feierberg, Isabella, Nissink, J. Willem M., Chen, Hongming, Bajorath, Jürgen, and Engkvist, Ola

Subjects
"Marie Sklodowska-Curie Actions"
Abstract

A significant challenge in high-throughput screening (HTS) campaigns is the identification of assay technology interference compounds. A Compound Interfering with an Assay Technology (CIAT) gives false readouts in many assays. CIATs are often considered viable hits and investigated in follow-up studies, thus impeding research and wasting resources. In this study, we developed a machine-learning (ML) model to predict CIATs for three assay technologies. The model was trained on known CIATs and non-CIATs (NCIATs) identified in artefact assays and described by their 2D structural descriptors. Usual methods identifying CIATs are based on statistical analysis of historical primary screening data and do not consider experimental assays identifying CIATs. Our results show successful prediction of CIATs for existing and novel compounds and provide a complementary and wider set of predicted CIATs compared to BSF, a published structure-independent model, and to the PAINS substructural filters. Our analysis is an example of how well-curated datasets can provide powerful predictive models despite their relatively small size.

Published
2019

12. Discovery and Optimization of Allosteric Inhibitors of Mutant Isocitrate Dehydrogenase 1 (R132H IDH1) Displaying Activity in Human Acute Myeloid Leukemia Cells

Author

Jones, Stuart, Ahmet, Jonathan, Ayton, Kelly, Ball, Matthew, Cockerill, Mark, Fairweather, Emma, Hamilton, Nicola, Harper, Paul, Hitchin, James, Jordan, Allan, Levy, Colin, Lopez, Ruth, Mckenzie, Edward, Packer, Martin, Plant, Darren, Simpson, Iain, Simpson, Peter, Sinclair, Ian, Somervaille, Tim C P, Small, Helen, Spencer, Gary J, Thomson, Graeme, Tonge, Michael, Waddell, Ian, Walsh, Jarrod, Waszkowycz, Bohdan, Wigglesworth, Mark, Wiseman, Daniel H, and Ogilvie, Donald

Subjects
Models, Molecular, Manchester Cancer Research Centre, Dose-Response Relationship, Drug, Molecular Structure, ResearchInstitutes_Networks_Beacons/mcrc, Cell Differentiation, ResearchInstitutes_Networks_Beacons/manchester_institute_of_biotechnology, Isocitrate Dehydrogenase, Leukemia, Myeloid, Acute, Structure-Activity Relationship, Allosteric Regulation, Manchester Institute of Biotechnology, Drug Discovery, Tumor Cells, Cultured, Humans, Enzyme Inhibitors
Abstract

A collaborative high throughput screen of 1.35 million compounds against mutant (R132H) isocitrate dehydrogenase IDH1 led to the identification of a novel series of inhibitors. Elucidation of the bound ligand crystal structure showed that the inhibitors exhibited a novel binding mode in a previously identified allosteric site of IDH1 (R132H). This information guided the optimization of the series yielding submicromolar enzyme inhibitors with promising cellular activity. Encouragingly, one compound from this series was found to induce myeloid differentiation in primary human IDH1 R132H AML cells in vitro.

Published
2016

14. Identification and Characterization of Dual Inhibitors of the USP25/28 Deubiquitinating Enzyme Subfamily

Author

Wrigley, Jonathan D., primary, Gavory, Gerald, additional, Simpson, Iain, additional, Preston, Marian, additional, Plant, Helen, additional, Bradley, Jenna, additional, Goeppert, Anne U., additional, Rozycka, Ewelina, additional, Davies, Gareth, additional, Walsh, Jarrod, additional, Valentine, Andrea, additional, McClelland, Keeva, additional, Odrzywol, Krzysztofa Ewa, additional, Renshaw, Jonathan, additional, Boros, Joanna, additional, Tart, Jonathan, additional, Leach, Lindsey, additional, Nowak, Thorsten, additional, Ward, Richard A., additional, Harrison, Timothy, additional, and Andrews, David M., additional

Published
2017
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15. Discovery of Imidazo[1,2-a]pyridine Ethers and Squaramides as Selective and Potent Inhibitors of Mycobacterial Adenosine Triphosphate (ATP) Synthesis

Author

Tantry, Subramanyam J., primary, Markad, Shankar D., additional, Shinde, Vikas, additional, Bhat, Jyothi, additional, Balakrishnan, Gayathri, additional, Gupta, Amit K., additional, Ambady, Anisha, additional, Raichurkar, Anandkumar, additional, Kedari, Chaitanyakumar, additional, Sharma, Sreevalli, additional, Mudugal, Naina V., additional, Narayan, Ashwini, additional, Naveen Kumar, C. N., additional, Nanduri, Robert, additional, Bharath, Sowmya, additional, Reddy, Jitendar, additional, Panduga, Vijender, additional, Prabhakar, K. R., additional, Kandaswamy, Karthikeyan, additional, Saralaya, Ramanatha, additional, Kaur, Parvinder, additional, Dinesh, Neela, additional, Guptha, Supreeth, additional, Rich, Kirsty, additional, Murray, David, additional, Plant, Helen, additional, Preston, Marian, additional, Ashton, Helen, additional, Plant, Darren, additional, Walsh, Jarrod, additional, Alcock, Peter, additional, Naylor, Kathryn, additional, Collier, Matthew, additional, Whiteaker, James, additional, McLaughlin, Robert E., additional, Mallya, Meenakshi, additional, Panda, Manoranjan, additional, Rudrapatna, Suresh, additional, Ramachandran, Vasanthi, additional, Shandil, Radha, additional, Sambandamurthy, Vasan K., additional, Mdluli, Khisi, additional, Cooper, Christopher B., additional, Rubin, Harvey, additional, Yano, Takahiro, additional, Iyer, Pravin, additional, Narayanan, Shridhar, additional, Kavanagh, Stefan, additional, Mukherjee, Kakoli, additional, Balasubramanian, V., additional, Hosagrahara, Vinayak P., additional, Solapure, Suresh, additional, Ravishankar, Sudha, additional, and Hameed P, Shahul, additional

Published
2017
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16. Identification and Characterization of Dual Inhibitors of the USP25/28 Deubiquitinating Enzyme Subfamily

Author

Wrigley, Jonathan D., Gavory, Gerald, Simpson, Iain, Preston, Marian, Plant, Helen, Bradley, Jenna, Goeppert, Anne U., Rozycka, Ewelina, Davies, Gareth, Walsh, Jarrod, Valentine, Andrea, McClelland, Keeva, Odrzywol, Krzysztofa Ewa, Renshaw, Jonathan, Boros, Joanna, Tart, Jonathan, Leach, Lindsey, Nowak, Thorsten, Ward, Richard A., Harrison, Timothy, and Andrews, David M.

Abstract

The ubiquitin proteasome system is widely postulated to be a new and important field of drug discovery for the future, with the ubiquitin specific proteases (USPs) representing one of the more attractive target classes within the area. Many USPs have been linked to critical axes for therapeutic intervention, and the finding that USP28 is required for c-Myc stability suggests that USP28 inhibition may represent a novel approach to targeting this so far undruggable oncogene. Here, we describe the discovery of the first reported inhibitors of USP28, which we demonstrate are able to bind to and inhibit USP28, and while displaying a dual activity against the closest homologue USP25, these inhibitors show a high degree of selectivity over other deubiquitinases (DUBs). The utility of these compounds as valuable probes to investigate and further explore cellular DUB biology is highlighted by the demonstration of target engagement against both USP25 and USP28 in cells. Furthermore, we demonstrate that these inhibitors are able to elicit modulation of both the total levels and the half-life of the c-Myc oncoprotein in cells and also induce apoptosis and loss of cell viability in a range of cancer cell lines. We however observed a narrow therapeutic index compared to a panel of tissue-matched normal cell lines. Thus, it is hoped that these probes and data presented herein will further advance our understanding of the biology and tractability of DUBs as potential future therapeutic targets.

Published
2024
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17. Discovery of ATP-Competitive Inhibitors of tRNAIleLysidine Synthetase (TilS) by High-Throughput Screening

Author

Shapiro, Adam B., Plant, Helen, Walsh, Jarrod, Sylvester, Mark, Hu, Jun, Gao, Ning, Livchak, Stephania, Tentarelli, Sharon, and Thresher, Jason

Abstract

A novel, ultrahigh-throughput, fluorescence anisotropy–based assay was developed and used to screen a 1.4-million-sample library for compounds that compete with adenosine triphosphate (ATP) for binding to Escherichia colitRNAIlelysidine synthetase (TilS), an essential, conserved, ATP-dependent, tRNA-modifying enzyme of bacterial pathogens. TilS modifies a cytidine base in the anticodon loop of Ile2 tRNA by attaching lysine, thereby altering codon recognition of the CAU anticodon from AUG (methionine) to AUA (isoleucine). A scintillation proximity assay for the incorporation of lysine into Ile2 tRNA was used to eliminate false positives in the initial screen resulting from detection artifacts as well as compounds competitive with the fluorescent label instead of ATP, and to measure inhibitor potencies against E. coliand Pseudomonas aeruginosaTilS isozymes. The tRNAIlesubstrate for P. aeruginosaTilS was identified for the first time to enable these measurements. ATP-competitive binding of inhibitors was confirmed by one-dimensional ligand-observe nuclear magnetic resonance. A preliminary structure–activity relationship is shown for two inhibitor series.

Published
2014
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18. Discovery of a Novel Benzodiazepine Series of Cbl-b Inhibitors for the Enhancement of Antitumor Immunity.

Author

Boerth JA, Chinn AJ, Schimpl M, Bommakanti G, Chan C, Code EL, Giblin KA, Gohlke A, Hansel CS, Jin M, Kavanagh SL, Lamb ML, Lane JS, Larner CJB, Mfuh AM, Moore RK, Puri T, Quinn TR, Ye M, Robbins KJ, Gancedo-Rodrigo M, Tang H, Walsh J, Ware J, Wrigley GL, Reddy IK, Zhang Y, and Grimster NP

Abstract

Casitas B-lineage lymphoma proto-oncogene-b (Cbl-b) is a RING finger E3 ligase that is responsible for repressing T-cell, natural killer (NK) cell, and B-cell activation. The robust antitumor activity observed in Cbl-b deficient mice arising from elevated T-cell and NK-cell activity justified our discovery effort toward Cbl-b inhibitors that might show therapeutic promise in immuno-oncology, where activation of the immune system can drive the recognition and killing of cancer cells. We undertook a high-throughput screening campaign followed by structure-enabled optimization to develop a novel benzodiazepine series of potent Cbl-b inhibitors. This series displayed nanomolar levels of biochemical potency, as well as potent T-cell activation. The functional activity of this class of Cbl-b inhibitors was further corroborated with ubiquitin-based cellular assays., Competing Interests: The authors declare no competing financial interest., (© 2023 American Chemical Society.)

Published
2023
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19. Compound-Mediated Assay Interferences in Homogeneous Proximity Assays

Author

Coussens NP, Auld D, Roby P, Walsh J, Baell JB, Kales S, Hadian K, Dahlin JL, Markossian S, Grossman A, Brimacombe K, Arkin M, Auld D, Austin CP, Baell J, Chung TDY, Coussens NP, Dahlin JL, Devanarayan V, Foley TL, Glicksman M, Hall MD, Haas JV, Hoare SRJ, Inglese J, Iversen PW, Kales SC, Lal-Nag M, Li Z, McGee J, McManus O, Riss T, Saradjian P, Sittampalam GS, Tarselli M, Trask OJ Jr., Wang Y, Weidner JR, Wildey MJ, Wilson K, Xia M, and Xu X

Abstract

Homogeneous proximity assays are widely implemented in high-throughput screening (HTS) of small-molecule libraries for drug and probe discovery. Representative technologies include amplified luminescent proximity homogeneous assays (ALPHA, which is trademarked by PerkinElmer; also informally referred to as Alpha), Förster/fluorescence resonance energy transfer (FRET), time-resolved FRET (TR-FRET) and homogeneous time-resolved fluorescence (HTRF, which is trademarked by CisBio), bioluminescence resonance energy transfer (BRET), and scintillation proximity assays (SPA). While highly useful, these assay technologies are susceptible to a variety of technology-related compound-mediated interferences, most notably signal attenuation (e.g., through quenching, inner-filter effects, light scattering), signal emission (e.g., auto-fluorescence), and disruption of affinity capture components such as affinity tags and antibodies. These assays are also susceptible to more generalized compound-mediated interferences such as nonspecific reactivity and aggregation. This chapter describes (a) the basic principles of proximity assays, (b) common sources of compound-mediated assay interference in homogeneous proximity assays, and (c) counter-screens and other strategies to classify compound-mediated assay interferences in homogeneous proximity assays. This information should be useful for prioritizing bioactive compounds in homogeneous proximity assays for drug and chemical probe discovery.

Published
2004

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