Journal
ONCOTARGET
Volume 8, Issue 26, Pages 42510-42524Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.17207
Keywords
Eg5 inhibitor; antitumor agent; 1,5-disubstituted tetrazole; scaffold hopping; phenotypic screening
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Funding
- National Natural Scientific Foundation of China [31420103905, 81430056, 81372491]
- Lam Chung Nin Foundation
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Eg5 is a kinesin spindle protein that controls chromosomal segregation in mitosis and is thus a critical drug target for cancer therapy. We report the discovery of a potent, selective inhibitor of Eg5 designated YL001. YL001 was obtained through shape similarity based virtual screening, and it bears a 1,5-disubstituted tetrazole scaffold. YL001 exhibits favorable bioactivity in a variety of cancer cell lines, including taxol-resistant ovarian cancer and 6TG-resistant breast cancer cell lines. This compound inhibits tumor growth by 60% and significantly prolongs median survival time by more than 50% in a xenograft mouse model. YL001 blocks the ATPase activity of Eg5 and causes mitotic failure, ultimately resulting in apoptosis of cancer cells through activation of the caspase-3 pathway. Our findings demonstrate that YL001 is a potent antitumor agent that may be developed for cancer therapeutics.
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