Authors

J Reekes¹; L Parkinson¹; D Swift¹; L Hashmi¹; A Perotti¹; J Unitt¹; 
¹ Sygnature Discovery, UK

Discussion

High-throughput screening (HTS) of large, diverse chemical libraries with lead-like properties facilitates the identification of desirable chemical starting points for drug discovery projects. Using our chemical libraries, comprising 262,000 compounds with attractive lead-like properties, Sygnature Discovery offers HTS as part of a tailored integrated hit discovery platform that includes fragment and knowledge-based approaches. Our HTS system combines industry-leading laboratory automation (HighRes Biosolutions) with a fully integrated informatics platform (Titian Mosaic) and Genedata Screener® analysis software to enable high-fidelity screening. Here, we give an overview of our HTS capability since its initiation in 2019, including the breadth of target classes, therapeutic areas and assay technologies covered, library QC data and example screening data. This data encompasses an initial pilot screen of 1,600 compounds and the full primary campaign. The primary screen performed well (Z' and RZ’ both > 0.8) with an active rate of 1.2%. Following cheminformatic triage, re-test of 500 compounds gave an excellent re-test rate of 96%. These 500 compounds were subjected to a technology interference counter screen and this data informed the selection of 250 compounds for characterization of IC50, with several compounds reporting IC50s < 10 µM. As exemplified here, HTS campaigns at Sygnature Discovery consistently yield high-quality, robust data, with excellent confirmation of compound activity from the primary HTS assay. Screening campaigns at Sygnature Discovery have returned high-quality chemical starting points for our clients, with HTS-identified actives progressed into active-to-hit and lead optimization stages with 2 lead series approaching compound selection. Building on this success, our future strategy is to increase our compound library size, automation capacity and breadth of assay platforms.