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A public-private partnership that supports the discovery of new medicines through open access research.
PFI-7 Chemical probe for GID4, substrate-recognition subunit of the CTLH E3 ubiquitin-protein ligase complexThe probe and control can be requested by clicking here. For any inquiries please contact proberequests@thesgc.org.group newOverviewPfizer in collaboration with the SGC have developed PFI-7, a potent, cell active chemical probe for the E3 ligase GID4. PFI-7 binds potently to GID4 with KD = 0.08 μM (SPR) and displaces the known degron1 peptide in a NanoBRETTM assay with EC50 = 0.6 μM. PFI-7N is a closely related negative control with KD = 5 μM (SPR). A co-crystal structure has been deposited. Chemical probe/control pair We have further developed a handle PFI-E3H1 and a PEGylated analogue to show that the handle tolerates a substitution. These findings offers opportunities to synthesize proximity-inducing or degrader modalities2. In Vitro Potency [PFI-7] (μM) [PFI-7] (μM) Cell-based Assay DataA NanoBRET assay was used to show target engagement in cells. The interaction was between NanoLuc® tagged degrons and full-length GID4. Co-crystal structures Main features 1. PFI-7 bound to GID4 substrate-binding pocket 2. Structure overview 3. Overlap with substrate peptide References Cheng Dong, Heng Zhang, Li Li, Wolfram Tempel, Peter Loppnau & Jinrong Min. Molecular basis of GID4-mediated recognition of degrons for the Pro/N-end rule pathway. Nature Chemical Biology 14, 466-473 (2018). Aleša Bricelj, Christian Steinebach, Robert Kuchta, Michael Gütschow, and Izidor Sosič. E3 Ligase Ligands in Successful PROTACs: An Overview of Syntheses and Linker Attachment Points, https://doi.org/10.3389/fchem.2021.707317 ; Milka Kostic. Targeted Protein Degradation and Proximity-Based Pharmacology, https://doi.org/10.5281/zenodo.5534371 .
