Identification of an Aurora Kinase Inhibitor Specific for the Aurora B Isoform

• Published in: Cancer research (Chicago, Ill.) Ill.), 2013-01, Vol.73 (2), p.716-724
• Main Authors: HUA XIE, LEE, Mee-Hyun, HAITAO LI, WEIYA MA, LUBET, Ronald A, JIAN DING, BODE, Ann M, ZIGANG DONG, FENG ZHU, REDDY, Kanamata, CONG PENG, YAN LI, YOUNG LIM, Do, JOON KIM, Dong, XIANG LI, KANG, Soouk
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; Antineoplastic Agents - pharmacology; Apoptosis; Aurora Kinase A; Aurora Kinase B; Aurora Kinases; Benzodioxoles - pharmacology; Biological and medical sciences; Cell Cycle Checkpoints; Cell Line, Tumor; Dose-Response Relationship, Drug; Humans; Indoles - pharmacology; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Medical sciences; Mice; Mice, Nude; Pharmacology. Drug treatments; Polyploidy; Protein Kinase Inhibitors - pharmacology; Protein Serine-Threonine Kinases - antagonists & inhibitors; Tumors; Xenograft Model Antitumor Assays
• ISSN: 0008-5472; 1538-7445; 1538-7445
• DOI: 10.1158/0008-5472.CAN-12-2784

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.