Abstract B118: Through hit synergy and beyond! Integrating hit finding and direct to biology to shorten time to development candidate

Abstract Helicases have been implicated in the progression of microsatellite instability-high (MSI-H) tumours and therefore represent promising therapeutic targets. Our team has applied diverse techniques to expedite the discovery of novel small molecule inhibitors for this clinically relevant helicase target; delivering a development candidate in under 18 months. The strategy employed for fast and efficient hit finding harnessed our Hit Synergy platform, which combines distinct screening technologies to rapidly generate high-quality, structurally diverse hits. Deployment of multiple approaches in parallel, including high throughput screening (HTS), virtual screening (VS), and knowledge-based drug discovery (KBDD), while drawing upon our previous expertise in this target class, ensured we rapidly identified novel chemical hit matter. Distinct chemical matter from each strand of hit finding was successfully validated through orthogonal screening assays, tailored specifically to the target. In addition to this, a highly effective Direct-to-Crystallography strategy was employed using 10 mM HTS liquid stocks to quickly deliver bound structures, without re-synthesis or re-acquisition. Following hit validation, rapid hit expansion was achieved using high-throughput chemistry (HTC) and Direct-to-Biology approaches, closely integrated with traditional medicinal chemistry design. Idea generation for new chemical matter with optimized properties and prioritization of compound selection for library synthesis were supported by in silico approaches utilizing artificial intelligence (AI) models. Taken together, we have been able to deliver multiple compound series, showing cellular target engagement and picomolar activity in a clinically relevant MSI-H cell line, favourable ADME properties, and in vivo efficacy in a disease relevant animal model. Here, we will describe these approaches in more detail and demonstrate how the integrated use of these technologies can rapidly advance drug discovery projects toward clinical evaluation. Citation Format: Alexandra I J. Stowell, Megan Thompson, Graeme Walker, Denise Swift, Lyn Parkinson, Tarun Arya, Euan Fordyce, Kam Chohan, Jonathan Finlayson, Terence Wu, Daniel Clare, Allan Jordan, Raquel Faba Rodriguez, Christopher Pearce, Rebecca Morgan, Clare Wilson, Sarah Beck, Rachel Lawrence, Oliver Smith, Sam Forshaw. Through hit synergy and beyond! Integrating hit finding and direct to biology to shorten time to development candidate [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr B118.