A DNA-based PROTAC degrades CENPB in TKI-resistant lung cancer models
- CENPB, the sequence-specific DNA-binding protein at centromeres, is overexpressed in aggressive cancers, yet has no direct inhibitors.
- CENPB OligoTAC links a CENPB-binding oligodeoxynucleotide to an E3 ligase ligand, driving CENPB ubiquitination and proteasomal degradation, centromere disruption and apoptosis.
- It was active in NSCLC models resistant to first-, second- and third-generation TKIs, with little toxicity to normal cells, good serum stability and a favorable in vivo PK and tolerability profile.
💡 Points
Using the protein's own DNA recognition sequence as the warhead sidesteps the need for a small-molecule pocket, which is the appeal for transcription-factor-like targets. The open questions I would press on are delivery beyond mouse models, oligonucleotide manufacturing cost, and whether the selectivity for tumor over normal cells holds up when CENPB is expressed everywhere.
Centromere-Targeting Chimeras for Combating Cancer Drug Resistance ↗