Centromere-Targeting Chimeras for Combating Cancer Drug Resistance

Abstract Centromere protein B (CENPB), the only sequence-specific DNA-binding protein at centromeres, maintains chromosomal stability and accurate mitotic segregation. Its overexpression in aggressive cancers is associated with aneuploidy and poor prognosis, yet CENPB remains therapeutically underexplored because direct inhibitors are unavailable. Here, we develop CENPB OligoTAC, a DNA-based PROTAC comprising a CENPB-binding oligodeoxynucleotide linked to an E3 ligase ligand. CENPB OligoTAC induces ubiquitination and proteasomal degradation of CENPB, disrupting centromere integrity, causing chromosome mis-segregation, and activating apoptosis. It shows potent activity in preclinical non-small cell lung cancer models resistant to first-, second-, and third-generation tyrosine kinase inhibitors, while exhibiting minimal cytotoxicity toward normal cells and good serum stability. In vivo, CENPB OligoTAC demonstrates favorable pharmacokinetics, good tolerability, and no significant hematological changes. By exploiting cancer cells’ dependence on centromeric stability, this platform offers a novel strategy for selectively targeting aneuploid malignancies.