Why BRD9 PROTACs underperform in mice, and a humanized-E3 fix
- Widely used CRBN- and VHL-based BRD9 degraders such as dBRD9 and VZ185 are much less potent in mouse cells, even though BRD9 itself is highly conserved.
- The gap points to species differences in the E3 ligases, notably the Crbn I391 residue and structural variation in VHL, which likely hamper ternary complex formation.
- Expressing human CRBN or VHL, or introducing a CrbnI391V mutation, restored potency in mouse cells and improved BRD9 degradation in vivo.
💡 Points
Anyone who has watched a PROTAC look great in human lines and flat in a mouse efficacy study will recognize this. It is a reminder that degrader PK/PD in rodents can fail for E3 reasons rather than compound reasons, so a CrbnI391V or humanized-E3 model is worth setting up early. It also argues for profiling ternary complex formation across species before reading a negative in vivo result as a dead series.
Improving PROTAC-Mediated Degradation in Mouse Models: BRD9 as a Case Study ↗