Over the past decade extensive research has

Over the past decade, extensive research has been directed toward the discovery of Aurora-selective small-molecule inhibitors. As a result, a handful of Aurora inhibitors has been identified. Among them, 1 (VX-680) and 2 (SNS-314) have entered human clinical trials as pan-Aurora kinase inhibitors (Fig. 1), and 3 (MLN8237) and 4 (MK-5108) are undergoing clinical assessment as Aurora A specific inhibitors. As another clinical candidate drug, 5 (AZD1152) has been also reported to selectively inhibit Aurora B. Although several Aurora inhibitors have currently reached the clinical evaluation stage, the ideal inhibitor profile for therapeutic use has not yet been defined. As a part of our ongoing effort to develop Aurora kinase inhibitors, herein, we describe the design, synthesis, and biochemical evaluation of hinge-binder tethered 1,2,3-triazolylsalicylamide inhibitors.
Results and discussion
Conclusions In conclusion, we developed a series of novel hinge binder tethered 1,2,3-triazolylsalicylamide Aurora kinase inhibitors. Various alkynes capable of interacting with the hinge through hydrogen bonds were introduced by facile CuAAC click chemistry. Click chemistry offered rapid access to the diverse hinge binding structures. The representative 4-Aminobutyric acid 8a exhibited inhibitory activity against Aurora A kinase with an IC50 value of 0.284μM, and 8m showed an IC50 value of 0.364μM against Aurora B kinase. We believe that these compounds can be good candidates for further design of potent and selective antiproliferative agents targeting Aurora kinases.
Experimental
Acknowledgements This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future Planning (NRF-2015R1A2A2A01004511).
Introduction The Aurora kinase family is a subfamily of serine/threonine kinases that is essential for the regulation of centrosome maturation, mitotic spindle formation, chromosome segregation and cytokinesis during mitosis [1], [2]. The family includes three kinases designated as Aurora A, B, and C, which are very closely related in the kinase domain sequence. However, these kinases have quite different and nonoverlapping functions during mitosis [3]. Aurora A regulates the cell cycle and is associated with late S phase and entry into the M phase. It associates with the spindle poles and is involved in both centrosomal and acentrosomal spindle assembly [4], [5]. Aurora B localizes to the centromeres in prometaphase, and then relocates to the spindle midzone at anaphase. It has functions associated with histone phosphorylation and chromatin condensation in prophase, chromosome alignment and segregation, regulation of a mitotic checkpoint at metaphase and a role in cytokinesis [6]. Aurora C has similar functions as Aurora B [7]. The expressions of Aurora A and Aurora B are elevated in a variety of human cancers and are associated with poor prognosis [8]. The potential roles of Aurora kinases in regulating cell mitosis and tumorigenesis make them attractive targets for anticancer therapy [9]. Many Aurora kinase inhibitors have been developed and introduced into clinical trials, including VX-680/MK-0457, ZM447439, Hesperadin, MLN8054, MLN8237, and AZD1152 (Fig. 1) [10], [11], [12]. ZM447439 [13], Hesperadin [14] and VX-680/MK-0457 [15] were the first generation of Aurora kinase inhibitors. These three small molecule chemical inhibitors occupy the ATP-binding site in Aurora kinases to inhibit catalytic activity. Unlike pan-Aurora kinase inhibitors, MLN8054 and MLN8237 are ATP-competitive and reversible Aurora A selective inhibitors, and are approximately 40-fold and 200-fold more sensitive towards Aurora A, respectively, compared with Aurora B [12]. MLN8237 is more potent than MLN8054 and causes less benzodiazepine-like side effects based on structure modulation by the addition of a methoxy group to either end of the MLN8054 molecule [16], [17]. AZD1152 is an Aurora B selective inhibitor that showed 1000-fold selectivity for Aurora B over Aurora A and a panel of 50 additional kinases in enzymatic assays [18], [19], [20], [21]. It thus still remains uncertain how exactly aurora A and B pan- or monospecific inhibitors induce tumor cell death and which type of inhibitor will be preferable from a therapeutic viewpoint. Recently, the research of novel selective Aurora inhibitors has become a new trend, and a lot of new active compounds have been developed [22], [23], [24].