Aliakbar Khalili Yazdi, Sumera Perveen, Cheng Dong, 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 and Dafydd R. Owen
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Chemical tools for the Gid4 subunit of the human E3 ligase C-terminal to LisH (CTLH) degradation complex†
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.
期刊介绍：
Research and review articles in medicinal chemistry and related drug discovery science; the official journal of the European Federation for Medicinal Chemistry.
In 2020, MedChemComm will change its name to RSC Medicinal Chemistry. Issue 12, 2019 will be the last issue as MedChemComm.
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