Structure-based design of novel pyrazoles as aurora kinase A inhibitors.

Abstract

AbstractInhibition of Aurora kinase, a member of serine/threonine kinase involved in the regulation of cell division is emerging as a new molecular targeted cancer treatment option. Three isoforms of Aurora kinase, A, B and C are known. Both Aurora A and B are over expressed in many human cancers and are linked to chromosome instability, oncogenic transformation, tumour progression and development of chemoresistance. Inhibitors of Aurora kinase, regardless of their kinase specificity spectrum have shown to promote cancer cell death by induction of apoptosis and mitotic catastrophe. Based on the current success of Aurora kinase inhibitors in the development of kinase-based cancer therapy, we have initiated a structure-based virtual screening for the identification of Aurora kinase inhibitors by using published aurora protein structure (PDB code:1MQ4). Small molecule and natural product compound libraries were docked into the active site/ATP binding site using the programs Gold 3.0 and Glide 4.5. A total of six compounds were identified with high priority scores through this method to possess Aurora A inhibition. One of the virtual screen (VS) hit, BPR1K0025S0 was synthesised in 3 steps and found to have Aurora A IC50~15 M and x-ray co-crystal structure in complex with the aurora protein was solved for this compound. Based on the binding mode of this compound to Aurora A protein, further modification in the ester part was envisaged and a total of around 40 compounds were synthesised. Many of them possessed enhanced activity level compared to the original hit. Of particular interest is the aniline series of compounds, which showed submicromolar activity in the enzyme based Aurora inhibition assay. Thus a forty-fold improvement in activity for BPR1K0269S0 was achieved from the initial virtual screen hit BPR1K0025S0.