Jadomycin B, an Aurora-B kinase inhibitor discovered through virtual screening

• Published in: Molecular cancer therapeutics Vol. 7; no. 8; pp. 2386 - 2393
• Main Authors: Fu, Da-Hua, Jiang, Wei, Zheng, Jian-Ting, Zhao, Gui-Yu, Li, Yan, Yi, Hong, Li, Zhuo-Rong, Jiang, Jian-Dong, Yang, Ke-Qian, Wang, Yanchang, Si, Shu-Yi
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research 01-08-2008
• Subjects: antitumor agent; Aurora Kinase B; Aurora Kinases; Aurora-B kinase inhibitor; Blotting, Western; Cell Line; Cell Proliferation - drug effects; Drug Evaluation, Preclinical; Flow Cytometry; Histones - antagonists & inhibitors; Histones - metabolism; Humans; Isoquinolines - chemistry; Isoquinolines - pharmacology; Jadomycin B; Molecular Structure; natural product; Phosphorylation; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Recombinant Proteins - antagonists & inhibitors; virtual screening
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-08-0035

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. [Mol Cancer
Ther 2008;7(7):2386–93]