Chemical tools for the Gid4 subunit of the human E3 ligase C-terminal to LisH (CTLH) degradation complex.
Aliakbar Khalili YazdiSumera PerveenCheng DongXiaosheng SongAiping DongMagdalena M SzewczykMatthew F CalabreseAgustin Casimiro-GarciaSubramanyam ChakrapaniMatthew S DowlingEmel FiciciJisun LeeJustin I MontgomeryThomas N O'ConnellGrzegorz J SkrzypekTuan P TranMatthew D TroutmanFeng WangJennifer A YoungJinrong MinDalia Barsyte-LovejoyPeter J BrownVijayaratnam SanthakumarCheryl H ArrowsmithMasoud VedadiDafydd R OwenPublished in: RSC medicinal chemistry (2024)
We have developed a novel chemical handle (PFI-E3H1) and a chemical probe (PFI-7) as ligands for the Gid4 subunit of the human E3 ligase CTLH degradation complex. Through an efficient initial hit-ID campaign, structure-based drug design (SBDD) and leveraging the sizeable Pfizer compound library, we identified a 500 nM ligand for this E3 ligase through file screening alone. Further exploration identified a vector that is tolerant to addition of a linker for future chimeric molecule design. The chemotype was subsequently optimized to sub-100 nM Gid4 binding affinity for a chemical probe. These novel tools, alongside the suitable negative control also identified, should enable the interrogation of this complex human E3 ligase macromolecular assembly.