AT9283, a novel aurora kinase inhibitor, suppresses tumor growth in aggressive B-cell lymphomas.

Abstract

Aurora kinases are oncogenic serine/threonine kinases that play key roles in regulating the mitotic phase of the eukaryotic cell cycle. Auroras are overexpressed in numerous tumors including B-cell non-Hodgkin's lymphomas and are validated oncology targets. AT9283, a pan-aurora inhibitor inhibited growth and survival of multiple solid tumors in vitro and in vivo. In this study, we demonstrated that AT9283 had potent activity against Aurora B in a variety of aggressive B-(non-Hodgkin lymphoma) B-NHL cell lines. Cells treated with AT9283 exhibited endoreduplication confirming the mechanism of action of an Aurora B inhibitor. Also, treatment of B-NHL cell lines with AT9283 induced apoptosis in a dose and time dependent manner and inhibited cell proliferation with an IC(50) < 1 μM. It is well known that inhibition of auroras (A or B) synergistically enhances the effects of microtubule targeting agents such as taxanes and vinca alkaloids to induce antiproliferation and apoptosis. We evaluated whether AT9283 in combination with docetaxel is more efficient in inducing apoptosis than AT9283 or docetaxel alone. At very low doses (5 nM) apoptosis was doubled in the combination (23%) compared to AT9283 or docetaxel alone (10%). A mouse xenograft model of mantle cell lymphoma demonstrated that AT9283 at 15 mg/kg and docetaxel (10 mg/kg) alone had modest anti-tumor activity. However, AT9283 at 20 mg/kg and AT9283 (15 or 20 mg/kg) plus docetaxel (10 mg/kg) demonstrated a statistically significant tumor growth inhibition and enhanced survival. Together, our results suggest that AT9283 plus docetaxel may represent a novel therapeutic strategy in B-cell NHL and warrant early phase clinical trial evaluation.

• Authors: Wenqing Qi, Xiaobing Liu, Laurence S Cooke, Daniel O Persky, Thomas P Miller, Matthew Squires, Daruka Mahadevan
• Journal: International journal of cancer (Int J Cancer) Vol. 130 Issue 12 Pg. 2997-3005 (Jun 15 2012) ISSN: 1097-0215 [Electronic] United States
• PMID: 21796626 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2011 UICC.

Chemical References

• 1-cyclopropyl-3-(3-(5-morpholin-4-ylmethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl)urea
• Antineoplastic Agents
• Benzimidazoles
• Protein Kinase Inhibitors
• Taxoids
• Docetaxel
• Urea
• AURKB protein, human
• Aurkb protein, mouse
• Aurora Kinase B
• Aurora Kinases
• Protein Serine-Threonine Kinases

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Apoptosis (drug effects)
• Aurora Kinase B
• Aurora Kinases
• Benzimidazoles (pharmacology)
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Docetaxel
• Humans
• Lymphoma, B-Cell (drug therapy, pathology)
• Lymphoma, Mantle-Cell (drug therapy)
• Mice
• Mice, SCID
• Protein Kinase Inhibitors (pharmacology)
• Protein Serine-Threonine Kinases (antagonists & inhibitors)
• Taxoids (pharmacology)
• Urea (analogs & derivatives, pharmacology)
• Xenograft Model Antitumor Assays