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2.
Nat Commun ; 12(1): 3962, 2021 06 25.
Article in English | MEDLINE | ID: mdl-34172723

ABSTRACT

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.


Subject(s)
Amyloid/antagonists & inhibitors , Antineoplastic Agents/pharmacology , Protein Aggregation, Pathological/metabolism , Tumor Suppressor Protein p53/metabolism , Amides/chemistry , Amides/pharmacology , Amides/therapeutic use , Amyloid/chemistry , Amyloid/metabolism , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/therapeutic use , Apoptosis/drug effects , Cell Cycle/drug effects , Cell Line, Tumor , Humans , Mice , Mutation , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/genetics , Neoplasms, Experimental/metabolism , Protein Aggregation, Pathological/drug therapy , Protein Domains , Pyridines/chemistry , Pyridines/pharmacology , Pyridines/therapeutic use , Transcription, Genetic/drug effects , Tumor Suppressor Protein p53/chemistry , Tumor Suppressor Protein p53/genetics
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