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

Loganathan Palanikumar, Laura Karpauskaite, Sarah Hassan, Maheen Alam, Mohamed Al-Sayegh, Ibrahim Chehade, Debabrata Maity, Liaqat Ali, Zackary Falls, Ram Samudrala, Mona Kalmouni, Yamanappa Hunashal, Jemil Ahmed, Shake Karapetyan, Renu Pasricha, Gennaro Esposito, Ahmed J. Afzal, Andrew D. Hamilton, Sunil Kumar, View ORCID ProfileMazin Magzoub
doi: https://doi.org/10.1101/2020.08.10.243154
Loganathan Palanikumar
1Biology Program, Division of Science, New York University Abu Dhabi, P.O. Box 129188, Saadiyat Island Campus, Abu Dhabi, United Arab Emirates
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Laura Karpauskaite
1Biology Program, Division of Science, New York University Abu Dhabi, P.O. Box 129188, Saadiyat Island Campus, Abu Dhabi, United Arab Emirates
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Sarah Hassan
1Biology Program, Division of Science, New York University Abu Dhabi, P.O. Box 129188, Saadiyat Island Campus, Abu Dhabi, United Arab Emirates
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Maheen Alam
2Department of Biology, SBA School of Science and Engineering, Lahore University of Management Sciences, Lahore, Pakistan
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Mohamed Al-Sayegh
1Biology Program, Division of Science, New York University Abu Dhabi, P.O. Box 129188, Saadiyat Island Campus, Abu Dhabi, United Arab Emirates
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Ibrahim Chehade
1Biology Program, Division of Science, New York University Abu Dhabi, P.O. Box 129188, Saadiyat Island Campus, Abu Dhabi, United Arab Emirates
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Debabrata Maity
3Department of Chemistry, New York University, New York, NY 10003, United States
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Liaqat Ali
4Core Technology Platforms, New York University Abu Dhabi, P.O. Box 129188, Saadiyat Island Campus, Abu Dhabi, United Arab Emirates
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Zackary Falls
5Department of Biomedical Informatics, School of Medicine and Biomedical Sciences, State University of New York (SUNY), Buffalo, NY 14203, USA
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Ram Samudrala
5Department of Biomedical Informatics, School of Medicine and Biomedical Sciences, State University of New York (SUNY), Buffalo, NY 14203, USA
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Mona Kalmouni
1Biology Program, Division of Science, New York University Abu Dhabi, P.O. Box 129188, Saadiyat Island Campus, Abu Dhabi, United Arab Emirates
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Yamanappa Hunashal
6Chemistry Program, Division of Science, New York University Abu Dhabi, P.O. Box 129188, Saadiyat Island Campus, Abu Dhabi, United Arab Emirates
7INBB, Viale Medaglie d’Oro, 305, 00136 Roma, Italy
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Jemil Ahmed
8Department of Chemistry and Biochemistry and Knoebel Institute for Healthy Aging, The University of Denver, Denver, CO 80210, United States
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Shake Karapetyan
9Physics Program, Division of Science, New York University Abu Dhabi, P.O. Box 129188, Saadiyat Island Campus, Abu Dhabi, United Arab Emirates
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Renu Pasricha
4Core Technology Platforms, New York University Abu Dhabi, P.O. Box 129188, Saadiyat Island Campus, Abu Dhabi, United Arab Emirates
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Gennaro Esposito
6Chemistry Program, Division of Science, New York University Abu Dhabi, P.O. Box 129188, Saadiyat Island Campus, Abu Dhabi, United Arab Emirates
7INBB, Viale Medaglie d’Oro, 305, 00136 Roma, Italy
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Ahmed J. Afzal
1Biology Program, Division of Science, New York University Abu Dhabi, P.O. Box 129188, Saadiyat Island Campus, Abu Dhabi, United Arab Emirates
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Andrew D. Hamilton
3Department of Chemistry, New York University, New York, NY 10003, United States
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  • For correspondence: mazin.magzoub@nyu.edu sunil.kumar97@du.edu andrew.hamilton@nyu.edu
Sunil Kumar
8Department of Chemistry and Biochemistry and Knoebel Institute for Healthy Aging, The University of Denver, Denver, CO 80210, United States
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  • For correspondence: mazin.magzoub@nyu.edu sunil.kumar97@du.edu andrew.hamilton@nyu.edu
Mazin Magzoub
1Biology Program, Division of Science, New York University Abu Dhabi, P.O. Box 129188, Saadiyat Island Campus, Abu Dhabi, United Arab Emirates
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  • ORCID record for Mazin Magzoub
  • For correspondence: mazin.magzoub@nyu.edu sunil.kumar97@du.edu andrew.hamilton@nyu.edu
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ABSTRACT

Missense mutations in p53 are severely deleterious and occur in over 50% of all human cancers. The vast 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 potently abrogates self-assembly of the aggregation-nucleating subdomain of mutant p53 DBD. Moreover, ADH-6 effectively 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 substantially shrinks xenografts harboring mutant p53 and prolongs survival, while exhibiting no toxicity to healthy tissue. This study demonstrates the first successful application of a bona fide small-molecule amyloid inhibitor as an anticancer agent.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted August 11, 2020.
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Protein mimetic amyloid inhibitor potently abrogates cancer-associated mutant p53 aggregation and restores tumor suppressor function
Loganathan Palanikumar, Laura Karpauskaite, Sarah Hassan, Maheen Alam, Mohamed Al-Sayegh, Ibrahim Chehade, Debabrata Maity, Liaqat Ali, Zackary Falls, Ram Samudrala, Mona Kalmouni, Yamanappa Hunashal, Jemil Ahmed, Shake Karapetyan, Renu Pasricha, Gennaro Esposito, Ahmed J. Afzal, Andrew D. Hamilton, Sunil Kumar, Mazin Magzoub
bioRxiv 2020.08.10.243154; doi: https://doi.org/10.1101/2020.08.10.243154
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Protein mimetic amyloid inhibitor potently abrogates cancer-associated mutant p53 aggregation and restores tumor suppressor function
Loganathan Palanikumar, Laura Karpauskaite, Sarah Hassan, Maheen Alam, Mohamed Al-Sayegh, Ibrahim Chehade, Debabrata Maity, Liaqat Ali, Zackary Falls, Ram Samudrala, Mona Kalmouni, Yamanappa Hunashal, Jemil Ahmed, Shake Karapetyan, Renu Pasricha, Gennaro Esposito, Ahmed J. Afzal, Andrew D. Hamilton, Sunil Kumar, Mazin Magzoub
bioRxiv 2020.08.10.243154; doi: https://doi.org/10.1101/2020.08.10.243154

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