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

  • Published:
  • Authors: Palanikumar, L., Karpauskaite, L., Al-Sayegh, M., Chehade, I., Alam, M., Hassan, S., Maity, D., Ali, L., Kalmouni, M., Hunashal, Y., Ahmed, J., Houhou T., Karapetyan, S., Falls, Z., Samudrala, R., Pasricha, R., Esposito, G., Afzal, AJ., Hamilton, AD., Kumar, S and Magzoub, M
  • Reference: Nat. Comm. 2021 June, 12 (1): 1-24. DOI: 10.1038/s41467-021-23985-1


Missense mutations in p53 are severely deleterious and occur in over 50% of all human cancers. The 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 abrogates self-assembly of the aggregation-nucleating subdomain of mutant p53 DBD. Moreover, ADH-6 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 effectively shrinks xenografts harboring mutant p53, while exhibiting no toxicity to healthy tissue, thereby substantially prolonging survival. This study demonstrates the successful application of a bona fide small-molecule amyloid inhibitor as a potent anticancer agent.