DNMT1 PROTAC B7 blocks catalytic and scaffolding roles in liver fibrosis
- DNMT1 drives fibrogenesis through both catalytic and non-catalytic mechanisms, so the team built PROTAC degraders starting from DC-517 to hit both at once.
- Lead compound B7 mediates ubiquitin-proteasome degradation of DNMT1, lowers global DNA methylation and suppresses profibrotic responses in vitro.
- In vivo, B7 reduced DNMT1 levels and attenuated liver fibrosis, with less collagen deposition and better hepatic function.
💡 Points
DNMT1 is a textbook case for degrading rather than inhibiting, because an active-site inhibitor leaves the scaffolding role untouched. My worry is selectivity for liver and what removing an essential maintenance methyltransferase does in dividing tissue; fibrosis models are forgiving on both counts.