Protein mimetic amyloid inhibitor potently abrogates cancer-associated mutant p53 aggregation and restores tumor suppressor function

• Published in: bioRxiv
• Main Authors: Loganathan Palanikumar, Karpauskaite, Laura, Hassan, Sarah, Alam, Maheen, Al-Sayegh, Mohamed, Chehade, Ibrahim, Maity, Debabrata, Ali, Liaqat, Falls, Zackary, Samudrala, Ram, Kalmouni, Mona, Hunashal, Yamanappa, Jemil Ahmed, Shake Karapetyan, Pasricha, Renu, Esposito, Gennaro, Afzal, Ahmed J, Hamilton, Andrew D, Kumar, Sunil, Magzoub, Mazin
• Format: Paper
• Language: English
• Published: Cold Spring Harbor Cold Spring Harbor Laboratory Press 11.08.2020; Cold Spring Harbor Laboratory
• Edition: 1.1
• Subjects: Alzheimer's disease; Apoptosis; Cancer Biology; Cell cycle; Diabetes mellitus; Hydrophobicity; Missense mutation; Mutants; Mutation; Neurodegenerative diseases; p53 Protein; Self-assembly; Toxicity; Transcription; Tumor suppressor genes; Xenografts; mutant p53; DNA-binding domain; pancreatic cancer; amyloid; protein aggregation; α-helix mimetics; cancer therapeutics; apoptosis; tumor suppressor; oligopyridylamides; cell cycle arrest
• ISSN: 2692-8205; 2692-8205
• DOI: 10.1101/2020.08.10.243154

Missense mutations in p53 are severely deleterious and occur in over 50% of all human cancers. The vast majority of these mutations are located in the inherently unstable DNA-binding domain (DBD), many of which destabilize the domain further and expose its aggregation-prone hydrophobic core, prompting self-assembly of mutant p53 into inactive cytosolic amyloid-like aggregates. Screening an oligopyridylamide library, previously shown to inhibit amyloid formation associated with Alzheimer's disease and type II diabetes, identified a tripyridylamide, ADH-6, that potently abrogates self-assembly of the aggregation-nucleating subdomain of mutant p53 DBD. Moreover, ADH-6 effectively targets and dissociates mutant p53 aggregates in human cancer cells, which restores p53's transcriptional activity, leading to cell cycle arrest and apoptosis. Notably, ADH-6 treatment substantially shrinks xenografts harboring mutant p53 and prolongs survival, while exhibiting no toxicity to healthy tissue. This study demonstrates the first successful application of a bona fide small-molecule amyloid inhibitor as an anticancer agent. Competing Interest Statement The authors have declared no competing interest.