Journal Article

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

Hunashal, Yamanappa, Karapetyan, Shake, Maity, Debabrata, Esposito, Gennaro, Hamilton, Andrew D., Kumar, Sunil, Palanikumar, L., Houhou, Tatiana, Ali, Liaqat, Samudrala, Ram, Hassan, Sarah, Karpauskaite, Laura, Alam, Maheen, Ahmed, Jemil, Pasricha, Renu, Falls, Zackary, Al-Sayegh, Mohamed, Afzal, Ahmed J., Kalmouni, Mona, Magzoub, Mazin, Chehade, Ibrahim

2021

Overview

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. Amyloid aggregation of mutant p53 contributes to its loss of tumor suppressor function and oncogenic gain-of-function. Here, the authors use a protein mimetic to abrogate mutant p53 aggregation and rescue p53 function, which inhibits cancer cell proliferation in vitro and halts tumor growth in vivo.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 101/6 / 13 / 13/1 / 13/106 / 13/109 / 13/2 / 13/31 / 13/51 / 14 / 14/28 / 14/34 / 14/63 / 147/143 / 38/77 / 38/91 / 631/154/309/2420 / 631/45/470/2284 / 631/57/2269 / 631/67/1059 / 631/92/613 / 64/60 / 82/58 / 82/80 / Agglomeration / Aggregates / Alzheimer's disease / Amides - chemistry / Amides - pharmacology / Amides - therapeutic use / Amyloid - antagonists & inhibitors / Amyloid - chemistry / Amyloid - metabolism / Animals / Anticancer properties / Antineoplastic Agents - chemistry / Antineoplastic Agents - pharmacology / Antineoplastic Agents - therapeutic use / Antitumor agents / Apoptosis / Apoptosis - drug effects / Biocompatibility / Cancer / Cell cycle / Cell Cycle - drug effects / Cell Line, Tumor / Cell proliferation / Diabetes mellitus / Humanities and Social Sciences / Humans / Hydrophobicity / Inhibitors / Mice / Missense mutation / multidisciplinary / Mutants / Mutation / Neoplasms, Experimental - drug therapy / Neoplasms, Experimental - genetics / Neoplasms, Experimental - metabolism / Neurodegenerative diseases / p53 Protein / Protein Aggregation, Pathological - drug therapy / Protein Aggregation, Pathological - metabolism / Protein Domains / Proteins / Pyridines - chemistry / Pyridines - pharmacology / Pyridines - therapeutic use / Science / Science (multidisciplinary) / Self-assembly / Toxicity / Transcription / Transcription, Genetic - drug effects / Tumor suppressor genes / Tumor Suppressor Protein p53 - chemistry / Tumor Suppressor Protein p53 - genetics / Tumor Suppressor Protein p53 - metabolism / Tumors / Xenografts / Xenotransplantation