DH166, a beta-carboline derivative, inhibits the kinase activity of PLK1.
A better way to treat complex diseases such as cancer is to aim for several targets at once. Beta-carboline derivatives have been shown to have anticancer activity, but these compounds may target several enzymes required for cell division. Polo-like kinases (PLKs) are well conserved serine/threonine kinases and PLK1 plays multiple roles in cell proliferation. Thus, PLK1 is one of the attractive mitotic targets for anticancer drugs. We found that DH166, a beta-carboline derivative, inhibits the growth of cdc5-2 temperature-sensitive mutant more profoundly than wild-type yeast cells. Because Cdc5 is the human PLK1 homologue in budding yeast, this observation indicates that DH166 might be a PLK1 inhibitor. Indeed, DH166 inhibits the kinase activity of purified PLK1 at low micromolar concentration in an ATP-competitive manner, which is consistent with the docking result based on the crystal structure of PLK1. In addition, DH166 blocks cancer cell proliferation, causes a mitotic arrest, increases cyclin B1 accumulation, induces aberrant mitotic spindles and apoptosis, presumably due to the downregulation of PLK1. Although beta-carboline derivatives have been demonstrated to show antitumor activities through multiple mechanisms, our data indicate for the first time that their cytotoxicity to tumor cells might be attributable to the inhibition of PLK1 as well.
Institute of Medicinal Biotechnology, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, China.
Jing
J
Zhang
Yan
Y
Li
Liang
L
Guo
Rihui
R
Cao
Pei
P
Zhao
Wei
W
Jiang
Qin
Q
Ma
Hong
H
Yi
Zhuorong
Z
Li
Jiandong
J
Jiang
Jialin
J
Wu
Yanchang
Y
Wang
Shuyi
S
Si
D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002243:Carbolines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray / Q000379:methods; D056744:Cyclin B1 / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008956:Models, Chemical; D008969:Molecular Sequence Data; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D008941:Spindle Apparatus; D000097869:Polo-Like Kinase 1
D000970:Antineoplastic Agents; D002243:Carbolines; D018797:Cell Cycle Proteins; D056744:Cyclin B1; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D000097869:Polo-Like Kinase 1; C551241:phenylpropyl-1-methyl-7-methoxyl-9-(3-chlorophenyl)-beta-carboline