2. Academic Validation
  3. Protein mimetic amyloid inhibitor potently abrogates cancer-associated mutant p53 aggregation and restores tumor suppressor function

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

  • Nat Commun. 2021 Jun 25;12(1):3962. doi: 10.1038/s41467-021-23985-1.
L Palanikumar 1,  Laura Karpauskaite 1,  Mohamed Al-Sayegh 1,  Ibrahim Chehade 1,  Maheen Alam 2,  Sarah Hassan 1,  Debabrata Maity 3,  Liaqat Ali 4,  Mona Kalmouni 1,  Yamanappa Hunashal 5 6,  Jemil Ahmed 7,  Tatiana Houhou 1,  Shake Karapetyan 8,  Zackary Falls 9,  Ram Samudrala 9,  Renu Pasricha 4,  Gennaro Esposito 5 10,  Ahmed J Afzal 1,  Andrew D Hamilton 11,  Sunil Kumar 12,  Mazin Magzoub 13
Affiliations

Affiliations

  • 1 Biology Program, Division of Science, New York University Abu Dhabi, Saadiyat Island Campus, Abu Dhabi, United Arab Emirates.
  • 2 Department of Biology, SBA School of Science and Engineering, Lahore University of Management Sciences, Lahore, Pakistan.
  • 3 Department of Chemistry, New York University, New York, NY, USA.
  • 4 Core Technology Platforms, New York University Abu Dhabi, Saadiyat Island Campus, Abu Dhabi, United Arab Emirates.
  • 5 Chemistry Program, Division of Science, New York University Abu Dhabi, Saadiyat Island Campus, Abu Dhabi, United Arab Emirates.
  • 6 DAME, Università di Udine, Udine, Italy.
  • 7 Department of Chemistry and Biochemistry and Knoebel Institute for Healthy Aging, The University of Denver, Denver, CO, USA.
  • 8 Physics Program, Division of Science, New York University Abu Dhabi, Saadiyat Island Campus, Abu Dhabi, United Arab Emirates.
  • 9 Department of Biomedical Informatics, School of Medicine and Biomedical Sciences, State University of New York (SUNY), Buffalo, NY, USA.
  • 10 INBB, Rome, Italy.
  • 11 Department of Chemistry, New York University, New York, NY, USA. andrew.hamilton@nyu.edu.
  • 12 Department of Chemistry and Biochemistry and Knoebel Institute for Healthy Aging, The University of Denver, Denver, CO, USA. sunil.kumar97@du.edu.
  • 13 Biology Program, Division of Science, New York University Abu Dhabi, Saadiyat Island Campus, Abu Dhabi, United Arab Emirates. mazin.magzoub@nyu.edu.
PMID: 34172723 DOI: 10.1038/s41467-021-23985-1
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.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z