A New Class of Molecular Glues: Double Allostery Restores KEAP1 Control of NRF2.

Key Points

• The study aims to investigate the effects of VVD-065, a new molecular glue, on the control of NRF2 by KEAP1.
• VVD-065 binds covalently to KEAP1 at Cys151.
• Assembly of KEAP1-CUL3 is enhanced to promote NRF2 degradation.
• The effects on NRF2-driven tumors were assessed.
• VVD-065 restored NRF2 ubiquitination and degradation.
• Enhanced KEAP1-CUL3 assembly was observed.
• NRF2-driven tumors were selectively suppressed.