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 |
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Pages (from-to) | 1050-1062 |
Number of pages | 13 |
Journal | Journal of Medicinal Chemistry |
Volume | 52 |
Issue number | 4 |
DOIs | |
Publication status | Published - 2009 Feb 26 |
All Science Journal Classification (ASJC) codes
- Molecular Medicine
- Drug Discovery