Scaffold-hopped BCL6 PROTAC degrades its target in DLBCL cells and works orally in xenografts
- Scaffold hopping from the BCL6 ligand BI-3802 gave a new tricyclic oxazinoquinolinone binder.
- Linker and CRBN-recruiter tuning produced compound 15, a PROTAC that degraded BCL6 quickly and potently, in a CRBN- and proteasome-dependent way.
- It strongly suppressed BCL6-dependent DLBCL cell growth, and oral dosing inhibited tumor growth in an OCI-LY1 xenograft without evident toxicity.
💡 Points
BI-3802 is a polymerizing degrader with a peculiar mechanism, so a conventional CRBN-recruiting PROTAC from a fresh tricyclic core is a useful alternative route to BCL6 removal. Oral efficacy matters most here; I'd want to see how the molecule balances size and permeability, and whether degradation depth tracks with tumor response across non-OCI-LY1 lines.