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.

Aurora-A and hBora Join the Game of Polo

“…An attractive alternative to inhibitors blocking the active site of Plk kinases is the development of compounds interfering with the binding abilities of the more diverse PBD domains, potentially yielding more selective inhibitors of Plk1 (27). Many other compounds with activities directed against Plk and Aurora kinases are now beginning to emerge (28)(29)(30)(31). Extensive research is clearly needed to validate specificities and relative efficiencies of all novel compounds.…”

Identification of ligand efficient, fragment-like hits from an HTS library: structure-based virtual screening and docking investigations of 2H- and 3H-pyrazolo tautomers for Aurora kinase A selectivity

“…Moreover, we have also recently reported a series of pyrazole Aurora kinase inhibitors bearing hydrazone side chain [25]. In several of these inhibitors, X-ray crystallography showed that the pyrazole ring is involved in the essential hydrogen bond interaction with the hinge region amino acid residues of Aurora kinase enzyme.…”

“…Analysis of these set of compounds revealed that some had a hydrazone functional group embedded in them. We have already reported several compounds bearing hydrazone fragments as Aurora kinase inhibitors, including those with pyrazole rings [14,25]. The pyrazole-hydrazones reported in ref 25 could not be further developed due to their chemical instability.…”

“…Selectivity for Aurora A over B or vice versa may be imparted to compounds which specifically interact with one of these residues. For example, we have already shown that the presence of the -NHCOCH 3 functional group in a series of pyrazole hydrazones could impart Aurora A selectivity by specific interaction with the Thr217 of Aurora A [25]. With this information in hand, we inspected the docked pose of taut-1 with both Auroras A and B for interaction with these four residues.…”

Computational Strategies in Cancer Drug Discovery

“…The goals of such methods include identifying effective modifications of existing lead compounds, as well as discovering novel lead compounds (de novo design). In recent years, several cases of successful applications of structure-based drug design have been reported (Combs 2007;Coumar et al 2009;Khan et al 2010;van Montfort and Workman 2009). Given the threedimensional structure of a target molecule, chemical compounds having potentially high affinity for this target can be designed rationally with the aid of computational methods.…”