p53 Y220C DUBTAC A1 is a bifunctional small molecule p53 Y220C-specific deubiquitinase-targeting chimera (DUBTAC) recruiting both p53 Y220C and the deubiquitinase OTUB1, effectively reactivates and deubiquitinates mutant p53 Y220C in vitro and in vivo.
A1 induced the upregulation of p53 Y220C protein in a dose-dependent manner in Huh7.
A1 could directly interact with p53 Y220C (KD=12.09 µM) in SPR assays.
A1 exhibited mutant-selective engagement with p53 Y220C, does not elevate p53 protein levels in wild-type or other mutant cell lines (R280K, R248W) even at 40 uM.
A1 exhibits potent anti-proliferative efficacy specifically in Y220C-harboring Huh7 cells with IC50 of 1.13 uM.
A1 predominantly removes K48-linked polyubiquitination, whereas K63-linked ubiquitination remains largely unchanged.
A1 (i.v., 40 mg/kg) suppressed Huh7 cells xenograft growth in vivo, upregulated the p53 Y220C protein by approximately 9-fold, significantly increased its downstream targets NOXA, PUMA, and p21.