Rapid Deployment of HTS, Delivering Validated Hits for a Helicase

Helicases are important enzymes in the progression of microsatellite instability-high (MSI-H) tumours. Despite significant advances in inhibitor design, many helicases remain undrugged with compounds displaying poor drug-like properties. As such, there remains a significant therapeutic need for the development of novel inhibitors of these targets.

We rapidly progressed a helicase drug discovery program, to deliver a pre-candidate molecule within 18 months of project initiation. Sygnature Discovery’s Hit Synergy platform, alongside our expertise in this target class, was deployed to rapidly identify novel, allosteric, small molecule inhibitors of the helicase of interest. Of note a chemically distinct series of hits were identified using high throughput screening (HTS) and were validated through a combination of orthogonal assays and a highly effective Direct-to-Crystal (D2C) strategy. The screening cascade deployed at the Hit Potency phase of the HTS was used to assess for and deliver early MOA insights and binding mechanism, prioritizing HTS compounds for rapid follow up.

High-quality HTS hits were delivered in just 6 months, with validation completed in under 10 months. Our innovative Direct-to-Crystal workflow, using HTS liquid stocks, eliminated costly compound re-purchase and enabled rapid SAR expansion. This approach delivered validated hits with well-defined protein binding modes, informing SAR and accelerated progression through the H2L phase.