Compound was docked into the
Compound was docked into the active site of Aurora B kinase using Tripos sybyl-X ver. 2.1.1. The crystal structure of human Aurora B kinase cocrystallized with its potent inhibitor VX-680 was used for the docking analysis (PDB ID: ). The most likely binding conformations were selected based on the docking score and the binding mode. In addition, the crystal structure of human Aurora A kinase (PDB ID: ) was aligned with Aurora B to provide a possible explanation for the selectivity of our compounds for Aurora B over Aurora A kinase (A). The binding mode of compound was similar to that of the reference compound VX-680 in the active site of Aurora B kinase. The nitrogen 74 of the benzoxazole ring and the amino group of the aminobenzoxazole moiety interacted with Tyr156 and Glu155 at the hinge backbone, which is considered to be a key interaction in the maintenance of the activity against kinases. The terminal aromatic ring substituted with a halogen atom reached up to near the DFG motif. Additionally, the carbonyl group of the urea linker formed a H-bond interaction with Lys106 at the β3 strand. As colored in blue and yellow in , respectively, Aurora A and B kinases have high sequence homology, however there is a critical difference at residue Glu161 in Aurora B (Thr217 in Aurora A), which can give different electrostatic and spatial states in the active site., In the active site of Aurora B, the oxygen atom of the alkoxybenzoxazole moiety could make an additional H-bond with Glu161 through a water molecule (B). This water-mediated H-bond interaction could be the cause of selectivity.
Cell proliferation assay was performed on various adenocarcinoma cell lines with the potent compounds and . GI values of compounds and ranged from 2.2 to 8.4μM (). In vivo antitumor activity of compound was evaluated against prostate cancer PC-3 xenograft tumors in nude mice (). Compound was subsequently dosed orally at 50mg/kg for 16days (qdx16). In vivo efficacy was assessed as reduction of tumor growth in -treated versus vehicle-treated mice. In contrast to the vehicle-treated mice, tumor growth suppression was observed in all mice that treated without significant loss of body weight or visible toxicity. Taken together, we provide as a potential lead compound for the development of wide range of Aurora B kinase inhibitor with better activity and safety profile.
A novel series of aminobenzoxazole analogs were designed and synthesized as Aurora B kinase inhibitors and their structure activity relationship was investigated. Some of the tested compounds revealed promising inhibitory activities against Aurora B kinase. Among these compounds, dichloro-substituted compound was the most potent. A molecular docking study suggested the putative binding mode of the most potent compound , implying the cause of the Aurora B selectivity. Compound showed antitumor activity against the human adenocarcinoma cell lines and PC-3 tumor xenograft model in vivo. This work provides an attractive lead for further structure optimization in the discovery of more selective and potent Aurora B kinase inhibitors.
We dedicate this article to Professor Young-Ger Suh on the occasion of his retirement. This research was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (No. 2011-0030074 and 2014R1A2A1A11052761).
Introduction In normal cells mitosis is strictly regulated to maintain a diploid chromosome content. In contrast most cancer cells are characterized by changes in the amount or organization of DNA due to errors in mitosis resulting in chromosome instability and aneuploidy . In fact, two characteristics of most cancer cells are (1) the loss of control of important regulatory cell cycle checkpoints and (2) a change in the organization or the amount of DNA compared with normal cells. Changes in DNA amount are mostly due to gains or losses of chromosomes as a result of incorrect segregation of chromosomes during mitosis. The segregation of the chromosomes is a complex process and involves the formation of a bipolar mitotic spindle guiding proper chromosome segregation. Considering the complexity of mitosis multiple checkpoint systems have been identified that ensure proper coordination. Progression through mitosis depends on three regulatory mechanisms: protein localization, proteolysis and phosphorylation performed by several serine/threonine kinases, known as mitotic kinases , . Several mitotic kinases are known to date including the Aurora kinases . They are frequently overexpressed in human tumors and were identified as a potential new mitotic target in cancer therapy.