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

摘要 药物发现和开发正经历着快速的变化， 提供新的潜在治疗来源的学术机构。随着这一变化， 为学术研究人员谁是知识渊博的所有步骤的翻译研究，以取得进展 化合物进入药物发现管道。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。我和李红玉博士设计了一个训练计划 这是我的目标，并提供了一个明确的路径来实现它们。 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，我们鉴定了TrkA 使用吡嗪基支架的激酶抑制剂。第二个项目的重点是开发一个图书馆， Flt 3激酶抑制剂使用实验室开发的新合成方法。额外的附带项目还 专注于开发新的合成方法来获取生物相关分子。 本论文所要完成的工作是一个综合性的翻译项目，旨在开发铅 具有针对CSF-1 R和Aurora B激酶的双重活性的化合物。最近发表的研究结果表明， 这两种激酶之间的间接联系可能导致协同抗癌活性。这两种激酶都是 验证乳腺癌的靶点，并开发对两者具有平衡活性的双重抑制剂， 为乳腺癌患者揭示了一种新的治疗模式。初步数据已确定化合物与 对CSF-1 R、Aurora B和c-Kit激酶具有强效活性。拟议的工作旨在开发化合物 优化为对CSF-1 R和Aurora B具有优于c-Kit的选择性。 博士后研究方向主要集中在通过在 体内功效研究。根据这项工作，将利用基于细胞的测定来研究以下生物学相互作用： CSF-1 R和Aurora B双重抑制。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。本提案中所述的工作强调了技术和 职业技能发展，我计划采取，以实现我的目标，成为一个学术独立调查员 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.