Discovery of New Catalytic Topoisomerase II Inhibitors for Anticancer Therapeutics.
androgen receptor
catalytic inhibitor
computer aided drug design
prostate cancer
topoisomerase II
Journal
Frontiers in oncology
ISSN: 2234-943X
Titre abrégé: Front Oncol
Pays: Switzerland
ID NLM: 101568867
Informations de publication
Date de publication:
2020
2020
Historique:
received:
24
11
2020
accepted:
15
12
2020
entrez:
18
2
2021
pubmed:
19
2
2021
medline:
19
2
2021
Statut:
epublish
Résumé
Poison inhibitors of DNA topoisomerase II (TOP2) are clinically used drugs that cause cancer cell death by inducing DNA damage, which mechanism of action is also associated with serious side effects such as secondary malignancy and cardiotoxicity. In contrast, TOP2 catalytic inhibitors induce limited DNA damage, have low cytotoxicity, and are effective in suppressing cancer cell proliferation. They have been sought after to be prospective anticancer therapies. Herein the discovery of new TOP2 catalytic inhibitors is described. A new druggable pocket of TOP2 protein at its DNA binding domain was used as a docking site to virtually screen ~6 million molecules from the ZINC15 library. The lead compound, T60, was characterized to be a catalytic TOP2 inhibitor that binds TOP2 protein and disrupts TOP2 from interacting with DNA, resulting in no DNA cleavage. It has low cytotoxicity, but strongly inhibits cancer cell proliferation and xenograft growth. T60 also inhibits androgen receptor activity and prostate cancer cell growth. These results indicate that T60 is a promising candidate compound that can be further developed into new anticancer drugs.
Identifiants
pubmed: 33598437
doi: 10.3389/fonc.2020.633142
pmc: PMC7883873
doi:
Types de publication
Journal Article
Langues
eng
Pagination
633142Informations de copyright
Copyright © 2021 Matias-Barrios, Radaeva, Song, Alperstein, Lee, Schmitt, Lee, Ban, Xie, Qi, Lallous, Gleave, Cherkasov and Dong.
Déclaration de conflit d'intérêts
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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