The discovery of a novel compound with potent antitumor activity: virtual screening, synthesis, biological evaluation and preliminary mechanism study
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Yuanyuan Jin1,*, Linhu Li1,*, Zhaoyong Yang1, Mingliang Liu1, Huiyuan Guo1, Weiyi Shen2
1Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
2Zhejiang Starry Pharmaceutical Co. Ltd., Xianju 317300, China
*These authors contributed equally to this work
Mingliang Liu, email: [email protected]
Weiyi Shen, email: [email protected]
Keywords: anti-tumor, synthesis, virtual screening, farnesyltransferase inhibitor
Received: December 15, 2016 Accepted: February 08, 2017 Published: February 21, 2017
Farnesyltransferase has been regarded as a promising drug target against cancer as it is critical for membrane association of several signal transduction proteins. In this study, a novel farnesyltransferase inhibitor (IMB-1406) was identified through virtual screening. It exhibits stronger potency (IC50s: 6.92–8.99 μM) than Sunitinib against all of the tested cancer cell lines. Preliminary studies on mechanism reveal that IMB-1406 induces apoptosis in HepG2 cells by arresting the cell cycle at the S phase, altering anti- and pro-apoptotic proteins leading to mitochondrial dysfunction and activation of caspase-3. This anti-tumor effect is most probably related to the inhibition of farnesyltransferase as indicated by molecular docking. Overall, IMB-1406 is a novel lead compound with potent antitumor activity and deserves further structural modifications.
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