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

L. Palanikumar, Laura Karpauskaite, Mohamed Al-Sayegh, Ibrahim Chehade, Maheen Alam, Sarah Hassan, Debabrata Maity, Liaqat Ali, Mona Kalmouni, Yamanappa Hunashal, Jemil Ahmed, Tatiana Houhou, Shake Karapetyan, Zackary Falls, Ram Samudrala, Renu Pasricha, Gennaro Esposito, Ahmed J. Afzal, Andrew D. Hamilton (), Sunil Kumar () and Mazin Magzoub ()
Additional contact information
L. Palanikumar: Saadiyat Island Campus
Laura Karpauskaite: Saadiyat Island Campus
Mohamed Al-Sayegh: Saadiyat Island Campus
Ibrahim Chehade: Saadiyat Island Campus
Maheen Alam: Lahore University of Management Sciences
Sarah Hassan: Saadiyat Island Campus
Debabrata Maity: New York University
Liaqat Ali: Saadiyat Island Campus
Mona Kalmouni: Saadiyat Island Campus
Yamanappa Hunashal: Saadiyat Island Campus
Jemil Ahmed: The University of Denver
Tatiana Houhou: Saadiyat Island Campus
Shake Karapetyan: Saadiyat Island Campus
Zackary Falls: State University of New York (SUNY)
Ram Samudrala: State University of New York (SUNY)
Renu Pasricha: Saadiyat Island Campus
Gennaro Esposito: Saadiyat Island Campus
Ahmed J. Afzal: Saadiyat Island Campus
Andrew D. Hamilton: New York University
Sunil Kumar: The University of Denver
Mazin Magzoub: Saadiyat Island Campus

Nature Communications, 2021, vol. 12, issue 1, 1-24

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-23985-1

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