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

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

Research output: Contribution to journal › Article › peer-review

10 Citations (Scopus)

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.

Original language	English
Pages (from-to)	4405-4408
Number of pages	4
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	27
Issue number	18
DOIs	https://doi.org/10.1016/j.bmcl.2017.08.016
Publication status	Published - 2017

Bibliographical note

Funding Information:
We would like to acknowledge funding from NIH R01 U54 HL127365 , the Linde center for chemical biology and the KU-KIST Graduate School of Converging Science and Technology Program.

Publisher Copyright:
© 2017 Elsevier Ltd

Keywords

Aurora kinase
Cancer
Mitosis
Pan-Aurora inhibitor
Selective kinase inhibitor

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.bmcl.2017.08.016

Cite this

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title = "Characterization of a highly selective inhibitor of the Aurora kinases",

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",

author = "Ferguson, {Fleur M.} and Doctor, {Zainab M.} and Apirat Chaikuad and Taebo Sim and Kim, {Nam Doo} and Stefan Knapp and Gray, {Nathanael S.}",

note = "Funding Information: We would like to acknowledge funding from NIH R01 U54 HL127365 , the Linde center for chemical biology and the KU-KIST Graduate School of Converging Science and Technology Program. Publisher Copyright: {\textcopyright} 2017 Elsevier Ltd",

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doi = "10.1016/j.bmcl.2017.08.016",

language = "English",

volume = "27",

pages = "4405--4408",

journal = "Bioorganic and Medicinal Chemistry Letters",

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T1 - Characterization of a highly selective inhibitor of the Aurora kinases

AU - Ferguson, Fleur M.

AU - Doctor, Zainab M.

AU - Chaikuad, Apirat

AU - Sim, Taebo

AU - Kim, Nam Doo

AU - Knapp, Stefan

AU - Gray, Nathanael S.

N1 - Funding Information: We would like to acknowledge funding from NIH R01 U54 HL127365 , the Linde center for chemical biology and the KU-KIST Graduate School of Converging Science and Technology Program. Publisher Copyright: © 2017 Elsevier Ltd

PY - 2017

Y1 - 2017

N2 - 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.

AB - 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.

KW - Aurora kinase

KW - Cancer

KW - Mitosis

KW - Pan-Aurora inhibitor

KW - Selective kinase inhibitor

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U2 - 10.1016/j.bmcl.2017.08.016

DO - 10.1016/j.bmcl.2017.08.016

M3 - Article

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AN - SCOPUS:85028763688

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VL - 27

SP - 4405

EP - 4408

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 18

ER -

Characterization of a highly selective inhibitor of the Aurora kinases

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

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