Unveiling the therapeutic potential of Ponatinib and Imatinib against Aurora Kinase A in gastric cancer cells

Abstract

Abstract Aurora kinase A (AURKA) is considered a promising therapeutic target because of its abnormal expression pattern in multiple cancers. Since AURKA possesses a high similarity in active binding site with other kinases, we attempted to investigate and rationalize several kinase inhibitors that are currently under preclinical and clinical settings. All such inhibitors were selected based on sequence and structural similarity of AURKA with other kinases. Molecular docking revealed that Ponatinib, Imatinib, GSK-2334470, CFI-400945, MK2 inhibitor 3, and Vemurafenib bound to AURKA with high affinity. Molecular Dynamic (MD) simulations were carried out to assess pocket druggability, and stability of the potential inhibitors with respect to binding free-energy calculations. The findings suggested stable binding, particularly, for Ponatinib and Imatinib with AURKA via Van der Waals interactions. We identified Leu139, Val147, Lys162, Tyr212, Gly216, Leu263, and Asp274 as hotspot residues for binding of the inhibitors. Further, in vitro analyses of Ponatinib and Imatinib along with positive control MLN8237 realized decrease in AURKA expression at genomic as well as protein level studies even after ectopic transfection of AURKA. Notably, these compounds also reduced the expression of related signaling molecules β-catenin, STAT3 and its phosphorylation and NF-𝜿B and its phosphorylation. Beside the negative influence exercised by inhibitors on the oncogenic effect such as cell proliferation and genomic instability, Ponatinib and Imatinib also induced apoptosis rescue by AURKA and enhanced the protein expression of apoptotic markers like Caspase 9, 8, 3 and PARP1. Our results suggest these compounds as promising molecules to be used against AURKA.