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 (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.
authors.affiliation: Division of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35 Keyan Road, Zhunan, Miaoli County 350, Taiwan, ROC.
authors.forename: Mohane Selvaraj
authors.initials: MS
authors.lastname: Coumar
authors.forename: Jiun-Shyang
authors.initials: JS
authors.lastname: Leou
authors.forename: Paritosh
authors.initials: P
authors.lastname: Shukla
authors.forename: Jian-Sung
authors.initials: JS
authors.lastname: Wu
authors.forename: Ajay Kumar
authors.initials: AK
authors.lastname: Dixit
authors.forename: Wen-Hsing
authors.initials: WH
authors.lastname: Lin
authors.forename: Chun-Yu
authors.initials: CY
authors.lastname: Chang
authors.forename: Tzu-Wen
authors.initials: TW
authors.lastname: Lien
authors.forename: Uan-Kang
authors.initials: UK
authors.lastname: Tan
authors.forename: Chun-Hwa
authors.initials: CH
authors.lastname: Chen
authors.forename: John T-A
authors.initials: JT
authors.lastname: Hsu
authors.forename: Yu-Sheng
authors.initials: YS
authors.lastname: Chao
authors.forename: Su-Ying
authors.initials: SY
authors.lastname: Wu
authors.forename: Hsing-Pang
authors.initials: HP
authors.lastname: Hsieh
mesh_terms: D000577:Amides; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D064096:Aurora Kinase A; D064107:Aurora Kinase B; D064127:Aurora Kinases; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D000577:Amides; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; C576917:AURKA protein, human; C576921:AURKB protein, human; D064096:Aurora Kinase A; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases