Matias-Barrios Victor M, Radaeva Mariia, Ho Chia-Hao, Lee Joseph, Adomat Hans, Lallous Nada, Cherkasov Artem, Dong Xuesen
The Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, 2660 Oak Street, Vancouver, BC V6H 3Z6, Canada.
Cancers (Basel). 2021 Jul 22;13(15):3675. doi: 10.3390/cancers13153675.
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.
临床上使用的拓扑异构酶II（TOP2）抑制剂是毒性抑制剂，可诱导DNA损伤导致癌细胞死亡。然而，它们也会破坏良性细胞，从而表现出严重的副作用，包括心脏毒性和药物诱导的继发性恶性肿瘤。需要具有不同作用机制（MOA）的新型TOP2抑制剂，如催化TOP2抑制剂，以更有效地控制肿瘤生长。我们已应用计算机辅助药物设计来开发一组新的小分子抑制剂，它们是我们之前鉴定的先导化合物T60的衍生物。特别是，化合物T638表现出改善的溶解性和微粒体稳定性。它是一种催化TOP2抑制剂，能有效抑制TOP2活性。T638具有一种新颖的作用机制，通过该机制它结合TOP2蛋白并阻断TOP2-DNA相互作用。T638强烈抑制癌细胞生长，但对细胞的遗传毒性有限。这些结果表明，T638是一种有前途的候选药物，值得进一步开发成临床使用的抗癌药物。
