2. Academic Validation
  3. Discovery and Structural Characterization of Small Molecule Binders of the Human CTLH E3 Ligase Subunit GID4

Discovery and Structural Characterization of Small Molecule Binders of the Human CTLH E3 Ligase Subunit GID4

  • J Med Chem. 2022 Oct 13;65(19):12725-12746. doi: 10.1021/acs.jmedchem.2c00509.
Chetan K Chana 1 2,  Pierre Maisonneuve 1,  Ganna Posternak 1,  Nicolas G A Grinberg 1 3,  Juline Poirson 4,  Samara M Ona 1 3,  Derek F Ceccarelli 1,  Pavel Mader 1,  Daniel J St-Cyr 5,  Victor Pau 1,  Igor Kurinov 6,  Xiaojing Tang 1,  Dongjing Deng 7,  Weiren Cui 7,  Wenji Su 7,  Letian Kuai 8,  Richard Soll 8,  Mike Tyers 9,  Hannes L Röst 4 10,  Robert A Batey 11,  Mikko Taipale 3 4,  Anne-Claude Gingras 1 3,  Frank Sicheri 1 2 3
Affiliations

Affiliations

  • 1 Lunenfeld-Tanenbaum Research Institute, Sinai Health, Toronto, Ontario M5G 1X5, Canada.
  • 2 Department of Biochemistry, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
  • 3 Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
  • 4 Donnelly Centre for Cellular and Biomolecular Research, Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 3E1, Canada.
  • 5 X-Chem Inc., Montréal, Québec H4S 1Z9, Canada.
  • 6 Department of Chemistry and Chemical Biology, Cornell University, NE-CAT, Argonne, Illinois 60439, United States.
  • 7 WuXi AppTec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China.
  • 8 WuXi AppTec, 55 Cambridge Parkway, 8th Floor, Cambridge, Massachusetts 02142, United States.
  • 9 Institute for Research in Immunology and Cancer, University of Montréal, Québec H3C 3J7, Canada.
  • 10 Department of Computer Science, University of Toronto, Toronto, Ontario M5S 2E4, Canada.
  • 11 Department of Chemistry, University of Toronto, Toronto, Ontario M5S 3H6, Canada.
PMID: 36117290 DOI: 10.1021/acs.jmedchem.2c00509
Abstract

Targeted protein degradation (TPD) strategies exploit bivalent small molecules to bridge substrate proteins to an E3 ubiquitin ligase to induce substrate degradation. Few E3s have been explored as degradation effectors due to a dearth of E3-binding small molecules. We show that genetically induced recruitment to the GID4 subunit of the CTLH E3 complex induces protein degradation. An NMR-based fragment screen followed by structure-guided analog elaboration identified two binders of GID4, 16 and 67, with Kd values of 110 and 17 μM in vitro. A parallel DNA-encoded library (DEL) screen identified five binders of GID4, the best of which, 88, had a Kd of 5.6 μM in vitro and an EC50 of 558 nM in cells with strong selectivity for GID4. X-ray co-structure determination revealed the basis for GID4-small molecule interactions. These results position GID4-CTLH as an E3 for TPD and provide candidate scaffolds for high-affinity moieties that bind GID4.

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