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

Palanikumar, L., Karpauskaite, Laura, Al-Sayegh, Mohamed, Chehade, Ibrahim, Alam, Maheen, Hassan, Sarah, Maity, Debabrata, Ali, Liaqat, Kalmouni, Mona, Hunashal, Yamanappa, Ahmed, Jemil, Houhou, Tatiana, Karapetyan, Shake, Falls, Zackary, Samudrala, Ram, Pasricha, Renu, Esposito, Gennaro, Afzal, Ahmed J., Hamilton, Andrew D., Kumar, Sunil, Magzoub, Mazin·2021·Nature Communications
DOI 10.1038/s41467-021-23985-1

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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.

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Metadata

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, A. J., Hamilton, A. D., Kumar, S., & Magzoub, M.
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2021-06-25
Volume
12
Issue
1
ISSN
2041-1723
DOI
10.1038/s41467-021-23985-1
Cited by
132
References
23
Language
en
Licence
Funders
New York University Abu Dhabi (Research Grant)

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CoChat. (2026). Citation check: Protein mimetic amyloid inhibitor potently abrogates cancer-associated mutant p53 aggregation and restores tumor suppressor function. https://app.cochat.ai/papers/10.1038/s41467-021-23985-1
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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, A. J., Hamilton, A. D., . . . Magzoub, M. (2021). Protein mimetic amyloid inhibitor potently abrogates cancer-associated mutant p53 aggregation and restores tumor suppressor function. Nature Communications. https://doi.org/10.1038/s41467-021-23985-1

Data sources

Bibliographic data: Semantic Scholar, OpenAlex, Crossref.

Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).

Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.