Structure-based drug design of novel aurora kinase a inhibitors: Structural basis for potency and specificity

Mohane Selvaraj Coumar; Jiun Shyang Leou; Paritosh Shukla; Jian Sung Wu; Ajay Kumar Dixit; Wen Hsing Lin; Chun Yu Chang; Tzu Wen Lien; Uan Kang Tan; Chun Hwa Chen; John T.A. Hsu; Yu Sheng Chao; Su Ying Wu; Hsing Pang Hsieh

doi:10.1021/jm801270e

Structure-based drug design of novel aurora kinase a inhibitors: Structural basis for potency and specificity

Mohane Selvaraj Coumar, Jiun Shyang Leou, Paritosh Shukla, Jian Sung Wu, Ajay Kumar Dixit, Wen Hsing Lin, Chun Yu Chang, Tzu Wen Lien, Uan Kang Tan, Chun Hwa Chen, John T.A. Hsu, Yu Sheng Chao, Su Ying Wu, Hsing Pang Hsieh

Center of Applied Nanomedicine

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

53 Citations (Scopus)

Abstract

Aurora kinases have emerged as attractive targets for the design of anticancer drugs. Through structure- based virtual screening, novel pyrazole hit 8a was identified as Aurora kinase A inhibitor (IC₅₀ = 15.1 μM). X-ray cocrystal structure of 8a in complex with Aurora A protein revealed the C-4 position ethyl carboxylate side chain as a possible modification site for improving the potency. On the basis of this insight, bioisosteric replacement of the ester with amide linkage and changing the ethyl substituent to hydrophobic 3-acetami- dophenyl ring led to the identification of 12w with a ∼450-fold improved Aurora kinase A inhibition potency (lC₅₀ = 33 nM), compared to 8a. Compound 12w showed selective inhibition of Aurora A kinase over Aurora B/C, which might be due to the presence of a unique H-bond interaction between the 3-acetamido group and the Aurora A nonconserved Thr217 residue, which in Aurora B/C is Glu and found to sterically clash with the 3-acetamido group in modeling studies.

Original language	English
Pages (from-to)	1050-1062
Number of pages	13
Journal	Journal of Medicinal Chemistry
Volume	52
Issue number	4
DOIs	https://doi.org/10.1021/jm801270e
Publication status	Published - 2009 Feb 26

All Science Journal Classification (ASJC) codes

Molecular Medicine
Drug Discovery

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Coumar, M. S., Leou, J. S., Shukla, P., Wu, J. S., Dixit, A. K., Lin, W. H., Chang, C. Y., Lien, T. W., Tan, U. K., Chen, C. H., Hsu, J. T. A., Chao, Y. S., Wu, S. Y., & Hsieh, H. P. (2009). Structure-based drug design of novel aurora kinase a inhibitors: Structural basis for potency and specificity. Journal of Medicinal Chemistry, 52(4), 1050-1062. https://doi.org/10.1021/jm801270e

Coumar, Mohane Selvaraj ; Leou, Jiun Shyang ; Shukla, Paritosh ; Wu, Jian Sung ; Dixit, Ajay Kumar ; Lin, Wen Hsing ; Chang, Chun Yu ; Lien, Tzu Wen ; Tan, Uan Kang ; Chen, Chun Hwa ; Hsu, John T.A. ; Chao, Yu Sheng ; Wu, Su Ying ; Hsieh, Hsing Pang. / Structure-based drug design of novel aurora kinase a inhibitors : Structural basis for potency and specificity. In: Journal of Medicinal Chemistry. 2009 ; Vol. 52, No. 4. pp. 1050-1062.

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title = "Structure-based drug design of novel aurora kinase a inhibitors: Structural basis for potency and specificity",

abstract = "Aurora kinases have emerged as attractive targets for the design of anticancer drugs. Through structure- based virtual screening, novel pyrazole hit 8a was identified as Aurora kinase A inhibitor (IC50 = 15.1 μM). X-ray cocrystal structure of 8a in complex with Aurora A protein revealed the C-4 position ethyl carboxylate side chain as a possible modification site for improving the potency. On the basis of this insight, bioisosteric replacement of the ester with amide linkage and changing the ethyl substituent to hydrophobic 3-acetami- dophenyl ring led to the identification of 12w with a ∼450-fold improved Aurora kinase A inhibition potency (lC50 = 33 nM), compared to 8a. Compound 12w showed selective inhibition of Aurora A kinase over Aurora B/C, which might be due to the presence of a unique H-bond interaction between the 3-acetamido group and the Aurora A nonconserved Thr217 residue, which in Aurora B/C is Glu and found to sterically clash with the 3-acetamido group in modeling studies.",

author = "Coumar, {Mohane Selvaraj} and Leou, {Jiun Shyang} and Paritosh Shukla and Wu, {Jian Sung} and Dixit, {Ajay Kumar} and Lin, {Wen Hsing} and Chang, {Chun Yu} and Lien, {Tzu Wen} and Tan, {Uan Kang} and Chen, {Chun Hwa} and Hsu, {John T.A.} and Chao, {Yu Sheng} and Wu, {Su Ying} and Hsieh, {Hsing Pang}",

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doi = "10.1021/jm801270e",

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Structure-based drug design of novel aurora kinase a inhibitors : Structural basis for potency and specificity. / Coumar, Mohane Selvaraj; Leou, Jiun Shyang; Shukla, Paritosh; Wu, Jian Sung; Dixit, Ajay Kumar; Lin, Wen Hsing; Chang, Chun Yu; Lien, Tzu Wen; Tan, Uan Kang; Chen, Chun Hwa; Hsu, John T.A.; Chao, Yu Sheng; Wu, Su Ying; Hsieh, Hsing Pang.

In: Journal of Medicinal Chemistry, Vol. 52, No. 4, 26.02.2009, p. 1050-1062.

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

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T1 - Structure-based drug design of novel aurora kinase a inhibitors

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AU - Coumar, Mohane Selvaraj

AU - Leou, Jiun Shyang

AU - Shukla, Paritosh

AU - Wu, Jian Sung

AU - Dixit, Ajay Kumar

AU - Lin, Wen Hsing

AU - Chang, Chun Yu

AU - Lien, Tzu Wen

AU - Tan, Uan Kang

AU - Chen, Chun Hwa

AU - Hsu, John T.A.

AU - Chao, Yu Sheng

AU - Wu, Su Ying

AU - Hsieh, Hsing Pang

PY - 2009/2/26

Y1 - 2009/2/26

N2 - Aurora kinases have emerged as attractive targets for the design of anticancer drugs. Through structure- based virtual screening, novel pyrazole hit 8a was identified as Aurora kinase A inhibitor (IC50 = 15.1 μM). X-ray cocrystal structure of 8a in complex with Aurora A protein revealed the C-4 position ethyl carboxylate side chain as a possible modification site for improving the potency. On the basis of this insight, bioisosteric replacement of the ester with amide linkage and changing the ethyl substituent to hydrophobic 3-acetami- dophenyl ring led to the identification of 12w with a ∼450-fold improved Aurora kinase A inhibition potency (lC50 = 33 nM), compared to 8a. Compound 12w showed selective inhibition of Aurora A kinase over Aurora B/C, which might be due to the presence of a unique H-bond interaction between the 3-acetamido group and the Aurora A nonconserved Thr217 residue, which in Aurora B/C is Glu and found to sterically clash with the 3-acetamido group in modeling studies.

AB - Aurora kinases have emerged as attractive targets for the design of anticancer drugs. Through structure- based virtual screening, novel pyrazole hit 8a was identified as Aurora kinase A inhibitor (IC50 = 15.1 μM). X-ray cocrystal structure of 8a in complex with Aurora A protein revealed the C-4 position ethyl carboxylate side chain as a possible modification site for improving the potency. On the basis of this insight, bioisosteric replacement of the ester with amide linkage and changing the ethyl substituent to hydrophobic 3-acetami- dophenyl ring led to the identification of 12w with a ∼450-fold improved Aurora kinase A inhibition potency (lC50 = 33 nM), compared to 8a. Compound 12w showed selective inhibition of Aurora A kinase over Aurora B/C, which might be due to the presence of a unique H-bond interaction between the 3-acetamido group and the Aurora A nonconserved Thr217 residue, which in Aurora B/C is Glu and found to sterically clash with the 3-acetamido group in modeling studies.

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Structure-based drug design of novel aurora kinase a inhibitors: Structural basis for potency and specificity

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