Elucidating the mechanism of ENaC activity reduction by molecular glue degrader drugs (NACFC 2026) - Sep 9, 2026 - Abstract #277; "Previous work has shown that the GSPT1/eRF3a-degrading MGDs CC-90009, SJ6986, and MRT-2359 reduce ENaC activity, but the seven additional MGDs used here did not at the doses tested. [1,3] CC-90009 reduces ENaC activity in a cereblon-dependent and GSPT1/eRF3a-independent fashion, suggesting that this mechanism leverages the cereblon-based ubiquitination and degradation of a neosubstrate involved in ENaC activity or regulation. Though we knocked down putative neosubstrates, this pathway remains unelucidated."
Cystic Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases • Targeted Protein Degradation • AVEN • CRBN • GSPT1
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E. Bulik-Sullivan 1; J. Galiger 2; R. Lee-Ferris 1; K. Venable 2; S. Lyons 3; A. Mordant 3; L. He 2; L. Herring 3; S. Randell 1
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