生物活性

• 描述NSC59984 is a mutant p53 reactivator, which can both restore wild-type p53 signaling through stimulation of transcription factor p73 and deplete mutant p53 GOF. NSC59984 at 25μM selectively restored p53-responsive transcriptional activity in mutant p53-expressing tumor cells, SW480 (mutant p53 R273H, P309S) and DLD-1 (mutant p53 S241F) cells, as endogenous protein levels of p21, Puma, Noxa, and DR5, target genes of p53, were significantly upregulated. NSC59984 induced cell death in tumor cells with EC50 values ranging in 8.38-110.49μM but not normal cells with little or no genotoxicity. NSC59984 induced mutant p53 protein degradation via MDM2 and the ubiquitin–proteasome pathway. NSC59984 treatment downregulated various mutant p53 proteins in a dose-dependent manner in SW480, DLD-1, Hop92 (mutant p53 R175L), and RXF393 cells (mutant p53 R175H). In contrast, wild-type p53 protein was upregulated in MRC-5 normal cells and HCT116 cancer cells treated with 50μM of NSC59984. Administration of NSC59984 at dose of 45mg/kg, i.p., significantly repressed DLD-1 xenograft tumor growth.
• 作用机制NSC59984 restores wild-type p53 signaling via p73 activation in mutant p53-expressing colorectal cancer cells.^[1]

• 动物研究
  剂量	Mice: 45 mg/kg[1] (i.p.)
  给药途径	i.p.