Characterization of a highly selective inhibitor of the Aurora kinases

Fleur M Ferguson; Zainab M Doctor; Apirat Chaikuad; Taebo Sim; Nam Doo Kim; Stefan Knapp; Nathanael S Gray

doi:10.1016/j.bmcl.2017.08.016

Characterization of a highly selective inhibitor of the Aurora kinases

Bioorg Med Chem Lett. 2017 Sep 15;27(18):4405-4408. doi: 10.1016/j.bmcl.2017.08.016. Epub 2017 Aug 10.

Authors

Fleur M Ferguson¹, Zainab M Doctor¹, Apirat Chaikuad², Taebo Sim³, Nam Doo Kim⁴, Stefan Knapp⁵, Nathanael S Gray⁶

Affiliations

¹ Department of Cancer Biology, Dana-Farber Cancer Institute, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
² Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, United Kingdom; Institute for Pharmaceutical Chemistry and Buchmann Institute for Life Sciences, Goethe University, Max-von Laue Str. 9, 60438 Frankfurt am Main, Germany.
³ Chemical Kinomics Research Center, Korea Institute of Science and Technology, Republic of Korea; KU-KIST Graduate School of Converging Science and Technology, Korea University, Republic of Korea.
⁴ Daegu-Gyeongbuk Medical Innovation Foundation, Republic of Korea.
⁵ Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, United Kingdom; German Cancer Consortium (DKTK), Frankfurt site, Germany; Institute for Pharmaceutical Chemistry and Buchmann Institute for Life Sciences, Goethe University, Max-von Laue Str. 9, 60438 Frankfurt am Main, Germany.
⁶ Department of Cancer Biology, Dana-Farber Cancer Institute, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA. Electronic address: Nathanael_Gray@dfci.harvard.edu.

PMID: 28818446
DOI: 10.1016/j.bmcl.2017.08.016

Abstract

Aurora kinases play an essential role in mitosis and cell cycle regulation. In recent years Aurora kinases have proved popular cancer targets and many inhibitors have been developed. The majority of these clinical candidates are multi-targeted, rendering them inappropriate as tools for studying Aurora kinase mediated signaling. Here we report discovery of a highly selective inhibitor of Aurora kinases A, B and C, with potent cellular activity and minimal off-target activity (PLK4). The X-ray co-crystal structure of Aurora A in complex with compound 2 is reported, and provides insights into the structural determinants of ligand binding and selectivity.

Keywords: Aurora kinase; Cancer; Mitosis; Pan-Aurora inhibitor; Selective kinase inhibitor.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Aurora Kinases / antagonists & inhibitors*
Aurora Kinases / metabolism
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Humans
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Structure-Activity Relationship

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
Aurora Kinases

Grants and funding

U54 HL127365/HL/NHLBI NIH HHS/United States