Identification of Dual CSF-1R/Aurora B Kinase Inhibitors as a Novel Breast Cancer Treatment Paradigm

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Abstract Drug discovery and development is undergoing rapid change toward an increasing dependency on academic institutions providing sources of new potential treatment. With this change, there is a growing need for academic researchers who are knowledgeable in all steps of translational research in order to progress compounds far into the drug discovery pipeline. It is my goal to become a professor focused on translational research and developing new treatments for cancer therapy. Dr. Hong-yu Li and I have devised a training plan that address my goals and provides a clear path to achieve them. The first portion of the training plan is the dissertation work already completed, which focused on developing a strong foundation in organic and medicinal chemistry. In the first project, we identified TrkA kinase inhibitors using a pyrazine based scaffold. The second project was centered on developing a library of Flt3 kinase inhibitors using novel synthetic methodology developed in the lab. Additional side projects also focused on developing new synthetic methodology to access biologically relevant molecules. The dissertation work to be completed is a comprehensive translational project aiming to develop lead compounds with dual activity against the CSF-1R and Aurora B kinases. Recently published findings suggest an indirect link between both kinases that could result in synergistic anti-cancer activity. Both kinases are validated targets for breast cancer, and developing dual inhibitors with balanced activity against both serves to unveil a novel treatment paradigm for breast cancer patients. Preliminary data has identified compounds with potent activity against CSF-1R, Aurora B, and c-Kit kinases. The proposed work aims to develop compounds optimized to have selectivity for CSF-1R and Aurora B over c-Kit. The postdoctoral research direction is focused on continuing to develop lead compounds through in vivo efficacy studies. In line with this work, cell based assays will be utilized to study the biological interplay of dual CSF-1R and Aurora B inhibition. Additionally, new projects will be pursued to develop additional skills in cancer biology and immunotherapy. The work described in this proposal highlights the steps for technical and career skill development I plan to take to achieve my goal of becoming an academic independent investigator and helping cancer patients in need.