(1209-B) Addition of Covalent Warhead and DEL-generated Hit Fragmentation empower Fragment-Based Drug Discovery
Monday, February 5, 2024
2:00 PM – 3:00 PM EST
Location: Exhibit Halls AB
Abstract: Fragment-Based Drug Discovery has long been recognized as one of the most powerful tools to interrogate protein targets in the small molecule drug discovery field. The basic rationale for FBDD is to utilize the appropriate assay format and library collection to screen out effective starting points for further evolution from hit expansion to lead discovery.
With the recent rise of covalent drugs, especially to explore strategies for hit discovery towards challenging targets, covalent fragment-based discovery is considered to be a breakthrough opportunity. Here WuXi AppTec reports on the assembly of a covalent fragment library that is suited to tackle protein targets via cysteine, serine, lysine, and tyrosine residues. In a case study we have screened a collection of covalent fragments against BTK (Bruton’s Tyrosine Kinase) by mass spectrometry. Several fragments were identified and orthogonally validated by biophysical and enzymatic assay, and eventually co-crystal structures enabled further structure-based drug design with medicinal chemistry strategies. Additionally, WuXi AppTec has utilized the information extracted from the DNA-encoded library (DEL) screen to serve as a neo-source of potential fragment hit identification, providing an alternative starting point for fragment optimization and evolution. DEL possesses natural traces of structure patterns in its chemical space. The dominating building blocks and pharmacophores enriched can be observed conspicuously among the screening data and be used in fragmentation analysis. We have conducted DEL-derived fragment validation and evolution on a newly developed E3 ligase GID4. Through several rounds of medicinal chemistry optimization, we eventually obtained lead-like compounds with improved IC50 and good ligand efficiency which provide an optimistic reference for potential new protein degrader development.