title: Jadomycin B, an Aurora-B kinase inhibitor discovered through virtual screening.
abstract: 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.
authors: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences/Peking Union Medical College, Tiantan Xili #1, Beijing, P.R. China.
authors: Da-Hua
authors: DH
authors: Fu
authors: Wei
authors: W
authors: Jiang
authors: Jian-Ting
authors: JT
authors: Zheng
authors: Gui-Yu
authors: GY
authors: Zhao
authors: Yan
authors: Y
authors: Li
authors: Hong
authors: H
authors: Yi
authors: Zhuo-Rong
authors: ZR
authors: Li
authors: Jian-Dong
authors: JD
authors: Jiang
authors: Ke-Qian
authors: KQ
authors: Yang
authors: Yanchang
authors: Y
authors: Wang
authors: Shu-Yi
authors: SY
authors: Si
mesh_terms: 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
chemical_list: 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