Journal of medicinal and pharmaceutical chemistry 2009-02-26

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

Index: J. Med. Chem. 52 , 1050, (2009)

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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 (IC(50) = 15.1 microM). 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-acetamidophenyl ring led to the identification of 12w with a approximately 450-fold improved Aurora kinase A inhibition potency (IC(50) = 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.