One atom flips a CRBN degrader from NSD2-selective to GSPT1-selective
- Starting from LLC0424, an NSD2 degrader that also engages GSPT1, a single-atom change gave two close analogues: 424-ND (NSD2-selective) and 424-GD (GSPT1-selective).
- 424-ND suppressed androgen receptor signaling in prostate cancer cells, while 424-GD triggered the integrated stress response.
- Biolayer interferometry showed distinct ternary-complex cooperativity for each target, and simulations suggested different low-energy conformations explain the bias.
💡 Points
Degrader selectivity here tracks ternary-complex cooperativity, not binary affinity, which is exactly what I'd want to see in an SAR table. A matched pair this tight is a ready-made probe set for NSD2 and GSPT1. I'd check proteome-wide selectivity and whether the cooperativity trend holds in cells.
Single-Atom Modification Enables Reversal of Degradation Selectivity between NSD2 and GSPT1 ↗