Aliakbar Khalili Yazdi; Sumera Perveen; Xiaosheng Song; Aiping Dong; Magdalena M. Szewczyk; Matthew F. Calabrese; Agustin Casimiro-Garcia; Subramanyam Chakrapani; Matthew S. Dowling; Emel Ficici; Jisun Lee; Justin I. Montgomery; Thomas N. O’Connell; Grzegorz J. Skrzypek; Tuan P. Tran; Matthew D. Troutman; Feng Wang; Jennifer A. Young; Jinrong Min; Dalia Barsyte-Lovejoy; Peter J. Brown; Vijayaratnam Santhakumar; Cheryl H. Arrowsmith; Masoud Vedadi; Dafydd R. Owen
bioRxiv, 2023
https://doi.org/10.1101/2023.11.13.566858

Abstract

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.