Jadomycin B, an Aurora-B kinase inhibitor discovered through virtual screening.
Aurora kinases have emerged as promising targets for cancer therapy because of their critical role in mitosis. These kinases are well-conserved in all eukaryotes, and IPL1 gene encodes the single Aurora kinase in budding yeast. In a virtual screening attempt, 22 compounds were identified from nearly 15,000 microbial natural products as potential small-molecular inhibitors of human Aurora-B kinase. One compound, Jadomycin B, inhibits the growth of ipl1-321 temperature-sensitive mutant more dramatically than wild-type yeast cells, raising the possibility that this compound is an Aurora kinase inhibitor. Further in vitro biochemical assay using purified recombinant human Aurora-B kinase shows that Jadomycin B inhibits Aurora-B activity in a dose-dependent manner. Our results also indicate that Jadomycin B competes with ATP for the kinase domain, which is consistent with our docking prediction. Like other Aurora kinase inhibitors, Jadomycin B blocks the phosphorylation of histone H3 on Ser10 in vivo. We also present evidence suggesting that Jadomycin B induces apoptosis in tumor cells without obvious effects on cell cycle. All the results indicate that Jadomycin B is a new Aurora-B kinase inhibitor worthy of further investigation.
Fu
Da-Hua
DH
Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences/Peking Union Medical College, Tiantan Xili #1, Beijing, P.R. China.
Jiang
Wei
W
Zheng
Jian-Ting
JT
Zhao
Gui-Yu
GY
Li
Yan
Y
Yi
Hong
H
Li
Zhuo-Rong
ZR
Jiang
Jian-Dong
JD
Yang
Ke-Qian
KQ
Wang
Yanchang
Y
Si
Shu-Yi
SY
D064107:Aurora Kinase B; D064127:Aurora Kinases; D015153:Blotting, Western; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D005434:Flow Cytometry; D006657:Histones / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D007546:Isoquinolines / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors
D006657:Histones; D007546:Isoquinolines; D047428:Protein Kinase Inhibitors; D011994:Recombinant Proteins; C081750:jadomycin B; C576921:AURKB protein, human; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases