a series of beta-carboline derivatives inhibit the kinase activity of plks一系列beta-carboline衍生品plk抑制激酶活性.pdfVIP

A Series of Beta-Carboline Derivatives Inhibit the Kinase Activity of PLKs 1. 1. 2 2 1 1 2 2 Xiaomin Han , Jing Zhang , Liang Guo , Rihui Cao , Yongzhen Li , Ni Li , Qin Ma , Jialin Wu *, 3 1 Yanchang Wang *, Shuyi Si * 1 Institute of Medicinal Biotechnology, Peking Union Medical College Chinese Academy of Medical Sciences, Beijing, People’s Republic of China, 2 Xinjiang Huashidan Pharmaceutical Co., Urumqi, People’s Republic of China, 3 Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, Florida, United States of America Abstract Polo-like kinases play an essential role in the ordered execution of mitotic events and 4 mammalian PLK family members have been identified. Accumulating evidence indicates that PLK1 is an attractive target for anticancer drugs. In this paper, a series of beta-carboline derivatives were synthesized and three compounds, DH281, DH285 and DH287, were identified as potent new PLK inhibitors. We employed various biochemical and cellular approaches to determine the effects of these compounds on the activity of PLK1 and other mitotic kinases and on cell cycle progression. We found that these three compounds could selectively inhibit the kinase activity of purified PLK1, PLK2 and PLK3 in vitro. They show strong antitumor activity against a number of cancer cell lines with relatively low micromolar IC50s, but are relatively less toxic to non-cancer cells (MRC5). Moreover, these compounds could induce obvious accumulation of HeLa cells in G /M and S phases and 2