Eg5 inhibitor YL001 induces mitotic arrest and inhibits tumor proliferation
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Yufei Wang1,2,*, Xingyu Wu1,*, Mufeng Du1, Xi Chen1, Xianling Ning1, Hong Chen1, Siyuan Wang1, Jia Liu1, Zhenming Liu2, Ridong Li1, Ge Fu2, Chunguang Wang2, Michael A. McNutt1, Demin Zhou2 and Yuxin Yin1
1Institute of Systems Biomedicine, State Key Laboratory of Natural and Biomimetic Drugs, Beijing Key Laboratory of Tumor Systems Biology, Department of Pathology, School of Basic Medicine, Peking-Tsinghua Center for Life Sciences, Peking University Health Science Center, Beijing 100191, China
2State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China
*These authors contributed equally to this work
Yuxin Yin, email: [email protected]
Demin Zhou, email: [email protected]
Keywords: Eg5 inhibitor, antitumor agent, 1,5-disubstituted tetrazole, scaffold hopping, phenotypic screening
Received: February 17, 2017 Accepted: April 05, 2017 Published: April 18, 2017
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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