Discovery of N-benzylbenzamide-based allosteric inhibitors of Aurora kinase A

Hyomin Lee; Euijung Kim; Narae Hwang; Jesik Yoo; Yunju Nam; Injeoung Hwang; Jin Gyeong Park; Sang Eun Park; Kyung Sook Chung; Hwan Won Chung; Chiman Song; Mi Jung Ji; Hyun Mee Park; In Kyun Lee; Kyung Tae Lee; Eun Joo Roh; Wooyoung Hur

doi:10.1016/j.bmc.2024.117658

Discovery of N-benzylbenzamide-based allosteric inhibitors of Aurora kinase A

Hyomin Lee, Euijung Kim, Narae Hwang, Jesik Yoo, Yunju Nam, Injeoung Hwang, Jin Gyeong Park, Sang Eun Park, Kyung Sook Chung, Hwan Won Chung, Chiman Song, Mi Jung Ji, Hyun Mee Park, In Kyun Lee, Kyung Tae Lee, Eun Joo Roh, Wooyoung Hur

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

4 Citations (Scopus)

Abstract

Aurora kinases (AurkA/B/C) regulate the assembly of bipolar mitotic spindles and the fidelity of chromosome segregation during mitosis, and are attractive therapeutic targets for cancers. Numerous ATP-competitive AurkA inhibitors have been developed as potential anti-cancer agents. Recently, a few allosteric inhibitors have been reported that bind to the allosteric Y-pocket within AurkA kinase domain and disrupt the interaction between AurkA and its activator TPX2. Herein we report a novel allosteric AurkA inhibitor (6h) of N-benzylbenzamide backbone. Compound 6h suppressed the both catalytic activity and non-catalytic functions of AurkA. The inhibitory activity of 6h against AurkA (IC₅₀ = 6.50 μM) was comparable to that of the most potent allosteric AurkA inhibitor AurkinA. Docking analysis against the Y-pocket revealed important pharmacophores and interactions that were coherent with structure–activity relationship. In addition, 6h suppressed DNA replication in G1-S phase, which is a feature of allosteric inhibition of AurA. Our current study may provide a useful insight in designing potent allosteric AurkA inhibitors.

Original language	English
Article number	117658
Journal	Bioorganic and Medicinal Chemistry
Volume	102
DOIs	https://doi.org/10.1016/j.bmc.2024.117658
Publication status	Published - 15 Mar 2024

Bibliographical note

Publisher Copyright:
© 2024 Elsevier Ltd

Keywords

Allosteric inhibitor
AurkA
Aurora kinase
TPX2
Y pocket

UN SDGs

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

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10.1016/j.bmc.2024.117658

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Lee, H., Kim, E., Hwang, N., Yoo, J., Nam, Y., Hwang, I., Park, J. G., Park, S. E., Chung, K. S., Won Chung, H., Song, C., Ji, M. J., Park, H. M., Lee, I. K., Lee, K. T., Joo Roh, E., & Hur, W. (2024). Discovery of N-benzylbenzamide-based allosteric inhibitors of Aurora kinase A. Bioorganic and Medicinal Chemistry, 102, Article 117658. https://doi.org/10.1016/j.bmc.2024.117658

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abstract = "Aurora kinases (AurkA/B/C) regulate the assembly of bipolar mitotic spindles and the fidelity of chromosome segregation during mitosis, and are attractive therapeutic targets for cancers. Numerous ATP-competitive AurkA inhibitors have been developed as potential anti-cancer agents. Recently, a few allosteric inhibitors have been reported that bind to the allosteric Y-pocket within AurkA kinase domain and disrupt the interaction between AurkA and its activator TPX2. Herein we report a novel allosteric AurkA inhibitor (6h) of N-benzylbenzamide backbone. Compound 6h suppressed the both catalytic activity and non-catalytic functions of AurkA. The inhibitory activity of 6h against AurkA (IC50 = 6.50 μM) was comparable to that of the most potent allosteric AurkA inhibitor AurkinA. Docking analysis against the Y-pocket revealed important pharmacophores and interactions that were coherent with structure–activity relationship. In addition, 6h suppressed DNA replication in G1-S phase, which is a feature of allosteric inhibition of AurA. Our current study may provide a useful insight in designing potent allosteric AurkA inhibitors.",

keywords = "Allosteric inhibitor, AurkA, Aurora kinase, TPX2, Y pocket",

author = "Hyomin Lee and Euijung Kim and Narae Hwang and Jesik Yoo and Yunju Nam and Injeoung Hwang and Park, {Jin Gyeong} and Park, {Sang Eun} and Chung, {Kyung Sook} and {Won Chung}, Hwan and Chiman Song and Ji, {Mi Jung} and Park, {Hyun Mee} and Lee, {In Kyun} and Lee, {Kyung Tae} and {Joo Roh}, Eun and Wooyoung Hur",

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doi = "10.1016/j.bmc.2024.117658",

language = "English",

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AU - Lee, Hyomin

AU - Kim, Euijung

AU - Hwang, Narae

AU - Yoo, Jesik

AU - Nam, Yunju

AU - Hwang, Injeoung

AU - Park, Jin Gyeong

AU - Park, Sang Eun

AU - Chung, Kyung Sook

AU - Won Chung, Hwan

AU - Song, Chiman

AU - Ji, Mi Jung

AU - Park, Hyun Mee

AU - Lee, In Kyun

AU - Lee, Kyung Tae

AU - Joo Roh, Eun

AU - Hur, Wooyoung

PY - 2024/3/15

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N2 - Aurora kinases (AurkA/B/C) regulate the assembly of bipolar mitotic spindles and the fidelity of chromosome segregation during mitosis, and are attractive therapeutic targets for cancers. Numerous ATP-competitive AurkA inhibitors have been developed as potential anti-cancer agents. Recently, a few allosteric inhibitors have been reported that bind to the allosteric Y-pocket within AurkA kinase domain and disrupt the interaction between AurkA and its activator TPX2. Herein we report a novel allosteric AurkA inhibitor (6h) of N-benzylbenzamide backbone. Compound 6h suppressed the both catalytic activity and non-catalytic functions of AurkA. The inhibitory activity of 6h against AurkA (IC50 = 6.50 μM) was comparable to that of the most potent allosteric AurkA inhibitor AurkinA. Docking analysis against the Y-pocket revealed important pharmacophores and interactions that were coherent with structure–activity relationship. In addition, 6h suppressed DNA replication in G1-S phase, which is a feature of allosteric inhibition of AurA. Our current study may provide a useful insight in designing potent allosteric AurkA inhibitors.

AB - Aurora kinases (AurkA/B/C) regulate the assembly of bipolar mitotic spindles and the fidelity of chromosome segregation during mitosis, and are attractive therapeutic targets for cancers. Numerous ATP-competitive AurkA inhibitors have been developed as potential anti-cancer agents. Recently, a few allosteric inhibitors have been reported that bind to the allosteric Y-pocket within AurkA kinase domain and disrupt the interaction between AurkA and its activator TPX2. Herein we report a novel allosteric AurkA inhibitor (6h) of N-benzylbenzamide backbone. Compound 6h suppressed the both catalytic activity and non-catalytic functions of AurkA. The inhibitory activity of 6h against AurkA (IC50 = 6.50 μM) was comparable to that of the most potent allosteric AurkA inhibitor AurkinA. Docking analysis against the Y-pocket revealed important pharmacophores and interactions that were coherent with structure–activity relationship. In addition, 6h suppressed DNA replication in G1-S phase, which is a feature of allosteric inhibition of AurA. Our current study may provide a useful insight in designing potent allosteric AurkA inhibitors.

KW - Allosteric inhibitor

KW - AurkA

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KW - TPX2

KW - Y pocket

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Discovery of N-benzylbenzamide-based allosteric inhibitors of Aurora kinase A

Abstract

Bibliographical note

Keywords

UN SDGs

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