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Protein mimetic amyloid inhibitor potently abrogates cancer-associated mutant p53 aggregation and restores tumor suppressor function
Link to bioRxiv paper:
http://biorxiv.org/cgi/content/short/2020.08.10.243154v1?rss=1
Authors: Palanikumar, L., Karpauskaite, L., Hassan, S., Alam, M., Al-Sayegh, M., Chehade, I., Maity, D., Ali, L., Falls, Z., Samudrala, R., Kalmouni, M., Hunashal, Y., Ahmed, J., Karapetyan, S., Pasricha, R., Esposito, G., Afzal, A. J., Hamilton, A. D., Kumar, S., Magzoub, M.
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.
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Link to bioRxiv paper:
http://biorxiv.org/cgi/content/short/2020.08.10.243154v1?rss=1
Authors: Palanikumar, L., Karpauskaite, L., Hassan, S., Alam, M., Al-Sayegh, M., Chehade, I., Maity, D., Ali, L., Falls, Z., Samudrala, R., Kalmouni, M., Hunashal, Y., Ahmed, J., Karapetyan, S., Pasricha, R., Esposito, G., Afzal, A. J., Hamilton, A. D., Kumar, S., Magzoub, M.
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.
Copy rights belong to original authors. Visit the link for more info