Chemical Tools for the Gid4 Subunit of the Human E3 Ligase C-terminal to LisH (CTLH) Degradation Complex

Aliakbar Khalili Yazdi; Sumera Perveen; Dong Cheng; Xiaosheng Song; Aiping Dong; Magdalena M. Szewczyk; Matthew F. Calabrese; Agustin Casimiro‐Garcia; Chakrapani Subramanyam; Matthew 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 Baršytė-Lovejoy; Peter J. Brown; Vijayaratnam Santhakumar; C.H. Arrowsmith; Masoud Vedadi; Dafydd R. Owen

doi:10.1039/d3md00633f

BiophysicsRSC Medicinal ChemistryJan 1, 2024

Peer-reviewed journal article

Chemical Tools for the Gid4 Subunit of the Human E3 Ligase C-terminal to LisH (CTLH) Degradation Complex

Aliakbar Khalili Yazdi, Sumera Perveen iD, Dong Cheng iD, Xiaosheng Song iD, Aiping Dong iD, Magdalena M. Szewczyk iD, Matthew F. Calabrese iD, Agustin Casimiro‐Garcia iD, Chakrapani Subramanyam iD, Matthew Dowling iD, Emel Ficici iD, Jisun Lee iD, Justin I. Montgomery, Thomas N. O’Connell, Grzegorz J. Skrzypek iD, Tuan P. Tran iD, Matthew D. Troutman, Feng Wang, Jennifer A. Young iD, Jinrong Min iD, Dalia Baršytė-Lovejoy iD, Peter J. Brown iD, Vijayaratnam Santhakumar iD, C.H. Arrowsmith iD, Masoud Vedadi iD, Dafydd R. Owen iD

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.

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