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

摘要 药物发现和开发正在经历快速变化，越来越依赖于 学术机构提供新的潜在治疗来源。随着这种变化，人们越来越需要 对翻译研究的所有步骤都了如指掌的学术研究人员 化合物进入了药物发现的管道。我的目标是成为一名专注于翻译的教授 研究和开发癌症治疗的新疗法。洪亮-余力博士和我制定了一个培训计划 这解决了我的目标，并为实现这些目标提供了一条明确的道路。 培训计划的第一部分是已经完成的论文工作，重点是 在有机化学和药物化学方面打下坚实的基础。在第一个项目中，我们确定了TrkA 使用以吡嗪为基础的支架的激酶抑制剂。第二个项目的中心是开发一个 利用实验室开发的新的合成方法开发的Flt3激酶抑制剂。其他附带项目也包括 专注于开发新的合成方法来获取生物相关分子。 本论文要完成的工作是一项旨在开发Lead的综合性翻译项目 具有抗CSF-1R和Aurora B激酶双重活性的化合物。最近发表的研究结果表明 这两种酶之间的间接联系可能导致协同抗癌活性。这两个激酶都是 乳腺癌的有效靶点，开发对两者具有平衡活性的双重抑制剂有助于 为乳腺癌患者推出一种新的治疗模式。初步数据已确定化合物与 对CSF-1R、Aurora B和c-Kit激酶具有很强的活性。这项拟议的工作旨在开发化合物 经过优化，对CSF-1R和Aurora B具有比c-Kit更高的选择性。 博士后的研究方向是继续开发先导化合物。 活体药效研究。与这项工作相一致，基于细胞的分析将被用来研究 双重CSF-1R和Aurora B抑制。此外，还将开展新的项目，以培养更多的技能。 癌症生物学和免疫疗法。本建议书中描述的工作重点介绍了技术和 我计划通过职业技能发展来实现我成为一名学术独立调查员的目标 帮助有需要的癌症患者。

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.