Protein mimetic amyloid inhibitor potently abrogates cancer-associated mutant p53 aggregation and restores tumor suppressor function
| Autor: | Laura Karpauskaite, Ahmed J. Afzal, Ibrahim Chehade, Jemil Ahmed, Renu Pasricha, Mazin Magzoub, Andrew D. Hamilton, Debabrata Maity, Mona Kalmouni, Loganathan Palanikumar, Sunil Kumar, Maheen Alam, Tatiana Houhou, Gennaro Esposito, Zackary Falls, Shake Karapetyan, Yamanappa Hunashal, Ram Samudrala, Mohamed Al-Sayegh, Liaqat Ali, Sarah Hassan |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Amyloid Cell cycle checkpoint Cancer therapy Transcription Genetic Pyridines Science Mutant General Physics and Astronomy Antineoplastic Agents Apoptosis Protein aggregation medicine.disease_cause Protein Aggregation Pathological General Biochemistry Genetics and Molecular Biology Article 03 medical and health sciences Mice 0302 clinical medicine Protein Domains Cell Line Tumor medicine Animals Humans Mutation Multidisciplinary Intrinsically disordered proteins Chemistry Small molecules Cell Cycle General Chemistry Neoplasms Experimental Amides Protein mimetic Cell biology 030104 developmental biology Cell culture 030220 oncology & carcinogenesis Structure-based drug design Tumor Suppressor Protein p53 |
| Zdroj: | Nature Communications, Vol 12, Iss 1, Pp 1-24 (2021) Nature Communications |
| ISSN: | 2041-1723 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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