About A public-private partnership that supports the discovery of new medicines through open access research. About SGC Partners Research Laboratories SGC-Toronto SGC-UNC SGC-Frankfurt SGC-Karolinska SGC-Neuro SGC-UCL Governance Collaborators Open Science Equity, Diversity and Inclusion Impact Science and Resources Proteins Structure Gallery Expression Vectors Plasmids Constructs Production Protocols ChromoHub Phylogenetic Trees UbiHub Phylogenetic Trees ChemBioPort Chemical Probes Program CHEMICAL PROBES Donated chemical probes Chemical Handles Human Kinase Chemical Probe Program ANTIBODIES TARGET ENABLING PACKAGES (TEPs) TISSUE PLATFORM Open Lab Notebooks PUBLICATIONS People Global Aled Edwards, CEO Susan McCormick, CFO Max Morgan, General Counsel and Public Policy Director SGC Toronto Cheryl Arrowsmith Dalia Barsyte-Lovejoy Takis Prinos Matthieu Schapira Levon Halabelian SGC UNC Tim Willson Alison Axtman David Drewry Peter J. Brown SGC UCL Mat Todd SGC Karolinska Michael Sundström SGC Frankfurt Stefan Knapp Susanne Müller-Knapp Thomas Hanke Vladimir Rogov Krishnal Saxena Andreas Joerger Václav Němec Andreas Krämer Sandra Röhm SGC Neuro Edward Fon Thomas Durcan Jean-François Trempe Ziv Gan-Or Peter McPherson Carl Laflamme Roxanne Lariviere News & Outreach News & Events News from SGC Press Releases Events Tweets by thesgconline
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 .
