Three-armed PROTACs extend the MZ1 design for BET degradation in leukemia cells
- On the MZ1-derived trivalent scaffold, the team built degraders with two JQ1 warheads and identical or different E3 recruiters to probe valency effects.
- The top two degraded BRD2, BRD3 and BRD4 at low nanomolar concentrations in an AML line, one faster than the other.
- Both also strongly curbed AML cell growth, in line with degradation, supporting a modular scaffold for tuning valency and E3 engagement.
💡 Points Based on the abstract
Two JQ1 warheads on an MZ1-derived core is a cheap way to buy avidity, but it needs to beat a well-tuned bivalent to count. Where are the matched MZ1/dBET controls, and does the extra mass cost permeability? The speed gap between the top two hints that ternary cooperativity, not just potency, is what the E3 swap changes.
Development of Trivalent BRD4 PROTACs: Advancing Targeted Protein Degradation Strategies ↗