DEVELOPMENT OF NOVEL SMALL MOLECULE INHIBITORS OF AURORA B KINASE SIGNALING

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Maintenance of chromosomal ploidy during cell division requires a precise coordination of chromosome segregation and cytokinesis such that the cleavage does not occur before all replicated sister chromatids are correctly attached to the mitotic spindle and anaphase has been initiated. A conserved multi-subunit factor termed the Chromosomal Passenger Complex (CPC) plays a central role in coordinating mitosis and cytokinesis through its functions at the kinetechore early in mitosis and at the spindle midzone during cytokinesis. Its essential role in cell division have made the catalytic subunit of the CPC, Aurora B kinase, an attractive chemotherapeutic target, and there are currently several Aurora inhibitors in clinical trials. These inhibitors target the highly conserved ATP-binding site and consequentially display only limited specificity, thus restricting their applicability for both research- and clinical applications. In contrast to the highly conserved catalytic site, the interaction between Aurora B and its activating scaffold, INCENP, is unique to these two proteins and represents a potential- but unexploited target for intervention. In this application we will take advantage of reagents and assays developed in the laboratory to screen for novel, allosteric disrupters of Aurora B activity for use as probes for research and clinical applications. The lines of experimentation that form the Specific Aims of this proposal will: 1) develop a high-=throughput, flow-cytometry-based screen to identify candidate small molecules that disrupt Aurora B/INCENP interations; and 2) apply a chemical biological approach to optimize the efficacy of these molecules both in vitro and in vivo. These experiments will be performed in collaboration wit the NM-INBre Chemical Biology & Screen Collaborative Core (CBSC), and the UNM Molecular Libraries Screening Center, where high-throughput flow cytometry has been developed for biochemical- and cell-based screening of chemical libraries. From these studies, it is anticipated that not only will novel reagents be developed for the study of cell division, but that these reagents will potentially translate into the clinical arena, where targeting of this critical structure represents an excellent target for chemotherapeutic intervention.