Optimization of New Catalytic Topoisomerase II Inhibitors as an Anti-Cancer Therapy

UBC Faculty Research and Publications

Optimization of New Catalytic Topoisomerase II Inhibitors as an Anti-Cancer Therapy Matias-Barrios, Victor M.; Radaeva, Mariia; Ho, Chia-Hao; Lee, Joseph; Adomat, Hans; Lallous, Nada; Cherkasov, Artem; Dong, Xuesen

Abstract

Clinically used topoisomerase II (TOP2) inhibitors are poison inhibitors that induce DNA damage to cause cancer cell death. However, they can also destroy benign cells and thereby show serious side effects, including cardiotoxicity and drug-induced secondary malignancy. New TOP2 inhibitors with a different mechanism of action (MOA), such as catalytic TOP2 inhibitors, are needed to more effectively control tumor growth. We have applied computer-aided drug design to develop a new group of small molecule inhibitors that are derivatives of our previously identified lead compound T60. Particularly, the compound T638 has shown improved solubility and microsomal stability. It is a catalytic TOP2 inhibitor that potently suppresses TOP2 activity. T638 has a novel MOA by which it binds TOP2 proteins and blocks TOP2–DNA interaction. T638 strongly inhibits cancer cell growth, but exhibits limited genotoxicity to cells. These results indicate that T638 is a promising drug candidate that warrants further development into clinically used anticancer drugs.

Item Metadata

Title	Optimization of New Catalytic Topoisomerase II Inhibitors as an Anti-Cancer Therapy
Creator	Matias-Barrios, Victor M.; Radaeva, Mariia; Ho, Chia-Hao; Lee, Joseph; Adomat, Hans; Lallous, Nada; Cherkasov, Artem; Dong, Xuesen
Contributor	Vancouver Prostate Centre
Publisher	Multidisciplinary Digital Publishing Institute
Date Issued	2021-07-22
Description	Clinically used topoisomerase II (TOP2) inhibitors are poison inhibitors that induce DNA damage to cause cancer cell death. However, they can also destroy benign cells and thereby show serious side effects, including cardiotoxicity and drug-induced secondary malignancy. New TOP2 inhibitors with a different mechanism of action (MOA), such as catalytic TOP2 inhibitors, are needed to more effectively control tumor growth. We have applied computer-aided drug design to develop a new group of small molecule inhibitors that are derivatives of our previously identified lead compound T60. Particularly, the compound T638 has shown improved solubility and microsomal stability. It is a catalytic TOP2 inhibitor that potently suppresses TOP2 activity. T638 has a novel MOA by which it binds TOP2 proteins and blocks TOP2–DNA interaction. T638 strongly inhibits cancer cell growth, but exhibits limited genotoxicity to cells. These results indicate that T638 is a promising drug candidate that warrants further development into clinically used anticancer drugs.
Subject	topoisomerase II; catalytic inhibitor; computer-aided drug design; cytotoxicity; DNA binding blocker
Genre	Article
Type	Text
Language	eng
Date Available	2021-08-11
Provider	Vancouver : University of British Columbia Library
Rights	CC BY 4.0
DOI	10.14288/1.0401367
URI	http://hdl.handle.net/2429/79272
Affiliation	Medicine, Faculty of; Other UBC; Urologic Sciences, Department of
Citation	Cancers 13 (15): 3675 (2021)
Publisher DOI	10.3390/cancers13153675
Peer Review Status	Reviewed
Scholarly Level	Faculty; Researcher
Rights URI	https://creativecommons.org/licenses/by/4.0/
Aggregated Source Repository	DSpace

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