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

Research output: Contribution to journalArticlepeer-review

64 Citations (Scopus)


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 languageEnglish
Pages (from-to)1050-1062
Number of pages13
JournalJournal of Medicinal Chemistry
Issue number4
Publication statusPublished - 2009 Feb 26

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery


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