| Literature DB >> 36117290 |
Chetan K Chana1,2, Pierre Maisonneuve1, Ganna Posternak1, Nicolas G A Grinberg1,3, Juline Poirson4, Samara M Ona1,3, Derek F Ceccarelli1, Pavel Mader1, Daniel J St-Cyr5, Victor Pau1, Igor Kurinov6, Xiaojing Tang1, Dongjing Deng7, Weiren Cui7, Wenji Su7, Letian Kuai8, Richard Soll8, Mike Tyers9, Hannes L Röst4,10, Robert A Batey11, Mikko Taipale3,4, Anne-Claude Gingras1,3, Frank Sicheri1,2,3.
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.Entities:
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Year: 2022 PMID： 36117290 PMCID： PMC9574856 DOI： 10.1021/acs.jmedchem.2c00509
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 8.039