Introduction

To identify and progress the most promising chemistry, and resolve the issues that inevitably arise, the right use of the right techniques at the right time is essential. This requires access to multiple techniques together with the expertise to run and interpret the results. This is a speciality at BioAscent and has developed by bringing together the use of biophysical, biochemical and cellular assays for over 150 molecular targets, providing corroborative and supportive data to create confidence in the results.

ASSAY CASCADE DESIGN CASE STUDIES

As part of our assay development/validation process we have developed a set of compounds known to cause interference in assays, so called PAINS activity, that can cause false positive results during screening (e.g. aggregators, redox cyclers, chelators etc.). We use these compounds during assay development to identify potential liabilities and can then either optimise the assay to minimise these ‘false positive’ effects, or in cases where these effects cannot be eliminated, we can put in place appropriate de-selection assays to quickly triage such compounds.

• KLK6: Synthesis and structure-activity relationship of N-(4-benzamidino)-oxazolidinones-potent and selective inhibitors of kallikrein-related peptidase 6. View case study, view paper.

• Characterisation of small molecule inhibitors of the Nrf2-Keap1 interaction using MicroScale Thermophoresis. View poster

• Reducing the PAINS in high throughput screening: assay design as a tool for maximising efficiency. View article.

• Using a library of Pan-Assay Interference (PAINS) small molecules to understand and improve HTS outcomes. View poster.

Key Expertise

Capabilities and Techniques

Our Experts

Publications

• Application of particle swarm optimization to understand mechanism of action of allosteric inhibitors of the enzyme HSD14ß13. A. Ford, F. Breitgoff, M. Pasquani, A. MacKenzie, S. McElroy, S. Baker, P. Abrusci, S. Varzandeh, L. Bird, A. Gavard, D. Damerell, M. Redhead. View paper.

• The identification and characterisation of autophagy inhibitors from the published kinase inhibitor sets. M. Zachari, J. Rainard, G. Pandarakalam, L. Robinson, J. Gillespie; M. Rajamanickam; V. Hamon; A. Morrison; I. Ganley; S. McElroy. View paper.

• Identification of a novel class of benzofuran oxoacetic acid-derived ligands that selectively activate cellular EPAC; Cells; 8(11); 1425; 2019. E. Beck, E. Parnell, A. Cowley, A. Porter J. Gillespie, J. Robinson, L. Robinson A. Pannifer, V. Hamon, P. Jones, A. Morrison, S. McElroy, M. Timmerman, H. Rutjes, P. Mahajan, J. Wiejak, U. Luchowska-Stańska, D. Morgan, G. Barker, H. Rehmann and S. Yarwood. View paper.

• Reducing the PAINS in high throughput screening: assay design as a tool for maximising efficiency; Drug Discovery World; Fall 2019, 53. S McElroy, P. Jones. View paper.

• Synthesis and structure–activity relationships of N-(4-benzamidino)-oxazolidinones–potent and selective inhibitors of kallikrein-related peptidase 6; chemRxiv DOI: 10.26434/chemrxiv.9788276, 2019. E. De Vita, N. Smits, H. van den Hurk, E. Beck, J. Hewitt, G. Baillie, E. Russell, A. Pannifer, V. Hamon, A.Morrison, S. McElroy, P. Jones, N. Ignatenko, N. Gunkel and A. Miller. View paper.

• A high-throughput screen for the identification of compounds that inhibit nematode gene expression by targeting spliced leader trans-splicing. Int J Parasitol Drugs Drug Resist. 2019 Apr 5;10:28-37. doi: 10.1016/j.ijpddr.2019.04.001. G. Pandarakalam, M. Speake, S. McElroy, A. Alturkistani, L. Philippe, J. Pettitt, B. Müller, B. Connolly. View paper.

• Targeting Quorum Sensing: High-Throughput Screening to Identify Novel LsrK Inhibitors. Int J Mol Sci. 2019 Jun 25;20(12). pii: E3112. doi: 10.3390/ijms20123112. V. Gatta, P. Ilina, A. Porter, S McElroy, P Tammela. View paper.

• Abstract LB-B17: Characterization of small molecule inhibitors of the Nrf2-Keap1 interaction using MicroScale Thermophoresis. Molecular Cancer Therapeutics 17 (1 Supplement), LB-B17-LB-B1. J. Rainard, A. Morrison, A. Pannifer, P. Jones, R. Mead, S. McElroy. View paper.

• Using Microscale Thermophoresis to Characterize Hits from High-Throughput Screening: A European Lead Factory Perspective. SLAS DISCOVERY: Advancing Life Sciences R&D, Vol 23, Issue 3, pp. 225 – 241. J. Rainard, G. Pandarakalam, S McElroy. View paper.

• Comprehensive Medicinal Chemistry III, Chapter 1.18, 505-519; Eds. S. Chackalamannil, D. Rotella, S. Ward; Oxford: Elsevier; 2017. European Lead Factory; F. Giordanetto, P. Jones, A. Nelson, J. Benningshof, G. Muller, A. Pannifer, S. van Boeckel and D. Tzalis. View paper.

• The SULSA Assay Development Fund: accelerating translation of new biology from academia to pharma. Drug Discovery Today, February 2017, Volume 22, Issue 2, Pages 199-203. S. McElroy, P. Jones, V. Barrault. View paper.

• In Vitro Assay Development and HTS of Small-Molecule Human ABAD/17beta-HSD10 Inhibitors as Therapeutics in Alzheimer’s Disease. SLAS Discovery, 2017, Volume 22, Issue 6, Pages 676-685. L. Aitken, G. Baillie, A. Pannifer, A. Morrison, P. Jones, T. Smith, S. McElroy, F. Gunn-Moore. View paper.

• Identification of a Novel, Small Molecule Partial Agonist for the Cyclic AMP Sensor, EPAC1. Nature Scientific Reports 7, 2017, Article number: 294. E. Parnell, S. McElroy, J. Wiejak, G. Baillie, A. Porter, D. Adams, H. Rehmann, B. Smith & S. Yarwood. View paper.

• The importance of triaging in determining the quality of output from high-throughput screening. Future Medicinal Chemistry, 2015, Vol. 7, No. 14, Pages 1847-1852. P. Jones, S. McElroy, A. Morrison, A. Pannifer. View paper.

Posters & case studies

• Using a library of Pan-Assay Interference (PAINS) small molecules to understand and improve HTS outcomes. G. Baillie, A. Morrison, A. Pannifer, S. McElroy. Download PDF.

• The use of Dynamic Mass Redistribution (DMR) in the European Lead Factory (ELF): a case study. G. Baillie, O. Watt, S. McElroy Download PDF

• Characterization of small molecule inhibitors of the Nrf2-Keap1 interaction using MicroScale Thermophoresis. J. Rainard, M. Matheson, J. Gemmell, A. Morrison, A. Pannifer, P. Jones, R. Mead, S. McElroy. Download PDF.

• The SULSA Assay Development Fund: a model for widening access to high throughput screening. S. McElroy, D. Barrault, P. Jones. Download PDF.

• The European Lead Factory: A Collaborative Approach to Drug Discovery. ESC Chemistry: F. MacLeod, A. Morrison, E. Beck, P. Jones, J. Hewitt, M. Matheson, J. Schulz, J. Robinson, L. Robinson, J. Gillespie, M. Huggett, M. Rajamanickam; ESC CMC: A. Pannifer, V. Hamon; ESC Biology: S. McElroy, M. Speake, G. Baillie, E. Russell, J. Rainard, A. Porter, G. Pandarakalam, N. Clark, D. Tegazzini. PPSC: H. Rutjes, C.A.A. van Boeckel, N. Smits, E. van Doornmalen, T. W. Lam, M. Bras, C. S. Schofield; J. J. Brem; M. A. McDonough, M. Van der Stelt, F. J. Janssen, P.P. Geurink, H. Ovaa, H. S. Overkleeft, A. C. M. van Esbroeck, M. P. Baggelaar, H. den Dulk. Download PDF.

• Lead generation: discovery of novel KLK6 Inhibitors as novel anti-cancer drugs. E. De Vita, N. Smits, H. van den Hurk, E. M. Beck, J. Hewitt, G. Baillie, E. Russell, A. Pannifer, V. Hamon, A.Morrison, S. P. McElroy, P. Jones, N. A. Ignatenko, N. Gunkel and A. K. Miller. View case study.