title: Identification of an Aurora kinase inhibitor specific for the Aurora B isoform.
abstract: Aurora kinases play an important role in chromosome alignment, segregation, and cytokinesis during mitosis. In the present study, we used a ligand docking method to explore the novel scaffold of potential Aurora B inhibitors. One thousand compounds from our in-house compound library were screened against the Aurora B structure and one compound, (E)-3-((E)-4-(benzo[d][1,3]dioxol-5-yl)-2-oxobut-3-en-1-ylidene)indolin-2-one (designated herein as HOI-07) was selected for further study. HOI-07 potently inhibited in vitro Aurora B kinase activity in a dose-dependent manner, without obvious inhibition of another 49 kinases, including Aurora A. This compound suppressed Aurora B kinase activity in lung cancer cells, evidenced by the inhibition of the phosphorylation of histone H3 on Ser10 in a dose- and time-dependent manner. This inhibition resulted in apoptosis induction, G(2)-M arrest, polyploidy cells, and attenuation of cancer cell anchorage-independent growth. Moreover, knocking down the expression of Aurora B effectively reduced the sensitivity of cancer cells to HOI-07. Results of an in vivo xenograft mouse study showed that HOI-07 treatment effectively suppressed the growth of A549 xenografts, without affecting the body weight of mice. The expression of phospho-histone H3, phospho-Aurora B, and Ki-67 was also suppressed in the HOI-07 treatment group. Taken together, we identified HOI-07 as a specific Aurora B inhibitor, which deserves further investigation.
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, Minnesota 55912, USA.
authors.forename: Hua
authors.initials: H
authors.lastname: Xie
authors.forename: Mee-Hyun
authors.initials: MH
authors.lastname: Lee
authors.forename: Feng
authors.initials: F
authors.lastname: Zhu
authors.forename: Kanamata
authors.initials: K
authors.lastname: Reddy
authors.forename: Cong
authors.initials: C
authors.lastname: Peng
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Do Young
authors.initials: DY
authors.lastname: Lim
authors.forename: Dong Joon
authors.initials: DJ
authors.lastname: Kim
authors.forename: Xiang
authors.initials: X
authors.lastname: Li
authors.forename: Soouk
authors.initials: S
authors.lastname: Kang
authors.forename: Haitao
authors.initials: H
authors.lastname: Li
authors.forename: Weiya
authors.initials: W
authors.lastname: Ma
authors.forename: Ronald A
authors.initials: RA
authors.lastname: Lubet
authors.forename: Jian
authors.initials: J
authors.lastname: Ding
authors.forename: Ann M
authors.initials: AM
authors.lastname: Bode
authors.forename: Zigang
authors.initials: Z
authors.lastname: Dong
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D064096:Aurora Kinase A; D064107:Aurora Kinase B; D064127:Aurora Kinases; D052117:Benzodioxoles / Q000494:pharmacology*; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D011123:Polyploidy; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
chemical_list: C579133:3-(4-(benzo(d)(1,3)dioxol-5-yl)-2-oxobut-3-en-1-ylidene)indolin-2-one; D000970:Antineoplastic Agents; D052117:Benzodioxoles; D007211:Indoles; D047428:Protein Kinase Inhibitors; C576921:AURKB protein, human; C576918:Aurka protein, mouse; C576924:Aurkb protein, mouse; D064096:Aurora Kinase A; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases