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DESIGN, SYNTHESIS AND IN‐VITRO EVALUATION OF ATP‐COMPETITIVE INHIBITORS OF AURORA KINASE‐A USING STRUCTURE‐BASED DRUG DESIGN (SBDD)

Aurora‐A kinase inhibitors are small molecule ATP – competitive inhibitors that have been emerged as promising chemotherapeutic agents for cancer. In this study, Structure‐based drug design (SBDD), is mainly used to investigate and to study the molecular interactions between selective ATP‐competitive inhibitor (alisertib) along with the proposed compounds and the existing X‐ray structure of Aurora‐A kinase protein (PDB: 2W1C). Based on SBDD, different proposed compounds (p‐aminobenzoic acid derivatives) were designed from alisertib (reference compound) by replacing the lipophilic moiety (benzazepine) with simpler lipophilic cyclic moieties, such as naphthalene, fluorene, and benzothiazole through amide bond as a linker. This structure‐based design was based on the primary interactions of alisertib with key residues of the hinge and hydrophobic regions of ATP‐binding site (Glu‐211, Ala‐213, Lys‐162, Val‐147, Leu‐139, and Leu‐263). p‐aminobenzoic acid derivatives were synthesized and their inhibitory activity was in‐vitro tested by PhosphoSens ® assay. All the designed p‐aminobenzoic acid compounds bound to the ATP‐active site and exhibited similar interactions as other scaffolds of Aurora‐A inhibitors. However, they presented less inhibitory activity against Aurora‐A compared to alisertib (IC50= 6 nM). Compound‐5 (IC50= 46μM) was the most active compound and will be further modified to enhance the inhibitory activity of Aurora‐A kinase.