(1011-B) A Comprehensive Helicase Offer to Expand Drug Discovery Horizons From Hit Finding to Lead Optimization

Abstract: Helicases are specialized and essential enzymes that unwind double-stranded DNA-DNA or RNA-DNA duplexes, which is critical for many vital cellular processes such as DNA replication, transcription, recombination, ribosome biogenesis and repair.
Recently these “undruggable targets” have become “hot targets” for drug development due to their overexpression in some cancer indications and in their key role in infectious mechanisms. Targeting helicases is a challenge for drug discovery due to their complexity, their close homology and their presence in all live cells as a key player in the maintenance of the genome integrity.
For these reasons, Eurofins Discovery has built comprehensive Helicase Integrated Drug Discovery solutions for Hit Finding, Hit-to-Lead and Lead Optimization, drawing on our extensive expertise in this target class, our robust assays and high-quality proteins.
The 20+ helicase platform of combines:
• High-quality proteins, compliant with screening assays and biophysics measurements
• HTS & profiling activity-based assays for ATPase and unwinding helicase activities
• Virtual screening capabilities
• Fragment based screening
• Off-the-shelf biophysics assays for binding confirmation and MoA studies
• Panels for selectivity and safety derisking
In this poster, we will present the helicase proteins and assays that have been developed to support drug discovery programs, focusing on the WRN helicase as an example. The WRN protein, produced in sf21 insect cells and N-Ter MBP tagged, has a purity of 81% and is compatible for screening and profiling activity assays, as well as biophysics binding assays (SPR, MST-TRIC, nanoDSF). Unwinding (fluorescent quench assay) and ATPase activity assays (using ADP Hunter™ Plus detection kit, Km=0.57nM; Reference inhibitor pIC50: NCS19630 pIC50=5.65; ML216 pIC50=5.09; Tyrphostin AG538 pIC50=5.73; Protoporphyrin pIC50=5.13) have been successfully implemented and are ready for profiling and final optimization for HTS.
By combining this Helicase Platform with other pre-clinical drug discovery capabilities, Eurofins Discovery’s experienced team of Scientific Project Leaders and Project Managers can support diverse drug discovery programs, enabling the rapid and efficient identification of the best drug candidates.