Successful hit finding for PIM3 kinase inhibitors: from HTS to extended hit characterisation including Spectral Shift technology
6 April 2023
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In this webinar, we will discuss the classical HTS approach and how Eurofins Discovery capabilities can help you to quickly and efficiently, initiate your Hit-to-Lead program.
The goal of drug discovery is clear: to identify the most promising hits and leads with drug-like properties in the shortest time. Successful preclinical candidates are ultimately selected by employing robust and reliable hit finding strategies. In this webinar, we will discuss the classical HTS approach and how Eurofins Discovery capabilities can help you to quickly and efficiently, initiate your Hit-to-Lead program. Using our PIM3 kinase (of particular interest in cancer treatment) programme we will illustrate how to validate innovative and tractable hit series. Our state-of-the-art hit finding platform boasts a comprehensive screening cascade and is made up of conventional screening technologies, as well as the most recent biophysics approaches: such as the Spectral Shift technology (MST-TRIC), in addition to ready-to-go selectivity and early ADME assays.
Methods & Results
Starting from a subset of 71,000 compounds from our 600,000-compound library, we identified 140 active hits using the ADP-Glo PIM3 activity assay. These hits were then confirmed using orthogonal assays (Biophysics, NanoBRETTM cellular target engagement assays). Using our kinase and ADME platforms, we investigated the selectivity of the hit for PIM3 versus PIM1 and PIM2, and documented their early ADME properties, identifying the most promising and selective series. Based on this cascade strategy, six clusters were selected.
Achievements & Further Applications
A robust screening cascade was successfully implemented to obtain highly selective and tractable kinase inhibitors within weeks. In doing so, we show that subsequent Hit-to-Lead and Lead Optimisation programmes can rapidly and efficiently generate safe preclinical candidates.
- Learn how to overcome challenge of kinase inhibitor development (selectivity, toxicity, safety issues) based on a comprehensive screening cascade
- Generate decision-making data with our high-value screening cascades to identify multiple novel and exciting series, increasing the chances of successfully discovering preclinical candidates that target oncology and metabolic disorders
- Save time and money using a robust hit finding strategy, with expert input and rapid turnaround times
- Broad range of assays, flexibility to create custom tests and cascades, adaptable to client needs
- Team of scientific experts with extensive experience in the Drug Discovery field
- How HTS cascades can help to identify novel and potent compounds.
Celine Legros, Drug Discovery Partnership Director, Eurofins Discovery
Celine Legros is a Drug Discovery Partnership Director at Eurofins Discovery. With extended knowledge of Eurofins Discovery’s expertise and services. She is the primary scientific contact for clients, deeply involved in the design of complex projects, such as HTS, Hit-to-Lead and Lead-Op programmes. Prior to joining Eurofins, Celine was Scientific Project Leader in the Screening Department at Institut de Recherches Servier, France, where she was responsible for designing and running screening cascades from Target to Hit/HTS through to Lead Optimisation. In close collaboration with chemistry and biophysics teams, Celine led screening projects in neuroscience, cardiovascular & metabolic diseases, immune-inflammation and oncology. In addition, she developed and ran assays on GPCRs, transcription factors, PPi, kinases, Ser-hydrolases and Tyr-kinase receptors, combining scientific relevance with robotics, data quality and throughput. Employing her expertise in HTS and previous experience in platform design, in close collaboration with robotics engineers, she designs automated platforms and implements new HTS technology. Celine holds a PhD in Animal Physiology (melatonin circanual rhythm and melatonin receptors) from the University of Tours, France, and completed a postdoctoral fellowship within the Blood Brain Barrier Group at King’s College London, UK.
Vanessa Porkolab, Biophysics Director, Eurofins Cerep
Vanessa Porkolab is leading Biophysics for drug discovery projects at Eurofins Cerep. Prior to joining as Biophysics Director in 2022, she was Project Leader in Biophysics in other European CROs and Biotechs working on Fragments, Small Molecules, Antibodies and Aptamer-based drug discovery programmes. With her scientific teams, she was involved in integrated projects spanning target validation, high-throughput screening campaigns and hit-to-lead to lead optimisation. She completed her PhD studies at Institut de Biologie Structurale (IBS) in Grenoble, France where she worked on multidisciplinary drug design projects targeting carbohydrate-based proteins involved in the immuneresponse. She then moved to Brandeis University near Boston, USA where her postdoctoral studies were focused on RNA display and biophysical characterisation of glycopeptides for anti-HIV Abs.
Philippe Dupuis, HTS Study Director, Eurofins Cerep
Philippe is a Drug Discovery Study Director at Eurofins Discovery and member of the Scientific Support. He joined Cerep and Eurofins Discovery more than 20 years ago. He is handling in vitro pharmacology studies for client drug discovery programmes (HTS, Hit to Lead, Lead Optimisation and Safety). In close collaboration with the clients and Lab Operation Departments, he ensures that the studies are conducted according to according to industry standards and agreed-upon study plans. He is also in charge of the Deliverables department to ease study results and reports upload to client databases. He received his PhD in Cellular and Molecular Biophysico-Chemistry (Cell to cell interaction and adhesion molecules) from the Center of Molecular Biophysic, University of Orléans, France.