[摘要]：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 mM). X-ray cocrystal structure of 8a in complex with Aurora A protein revealed the C-4 position Et 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 Et substituent to hydrophobic 3-acetamidophenyl ring led to the identification of 12w with a ~450-fold improved Aurora kinase A inhibition potency (IC50 = 33 nM), compared to 8a. Compd. 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.
