Medicinal Chemistry

这个白血病孢子应用程序的一个主要主题是转化研究，重点是识别 用于抗白血病药物发现的治疗相关靶点。本报告中介绍的每个项目 应用是临床医生和基础科学家之间强大合作努力的证明， 涉及转化研究的许多方面，包括致癌信号，表观遗传学，实验 治疗学和免疫学。药物化学核心整合了两个实验室的专业知识， 包括药物化学、分子和细胞生物学以及分子药理学（Chen）， 计算化学和结构生物学（Li）。在过去的几年里，该计划已经开发了一个 一系列针对临床上与白血病发生相关的不同分子缺陷的药物，其中两种是 准备在2009年进入临床试验因此，这个核心提供了一个平台， 从这些项目中的每一个到小分子试剂的设计和合成， 假设，并增加了一个重要的层面，以加快从板凳到诊所的翻译。 具体而言，以下三个目标构成了本药物化学核心的重点， 靶向肿瘤特异性T细胞和自然杀伤细胞的免疫调节（项目3），以及蛋白质 磷酸酶（PP）2A（试点项目2），将扩大到解决其他新的分子靶点 其他项目产生的。总体而言，我们的具体目标包括： 目标1.对来那度胺进行先导性优化，开发特异性免疫调节药物， 慢性淋巴细胞白血病（CLL）治疗（与项目3合作）。 目标2.对FTY 720进行结构优化，以开发新型PP 2A活化剂（ 试点项目2）。 目标3.提供药物化学方面的服务，包括定制合成，样品 计算化学和结构生物学的研究人员 SPORE应用程序（所有项目）和其他NCI SPORE和POL调查员。的示例 这是提供OSU-HDAC 42的研究人员在项目4，5和发展项目1。 总的来说，这个独特的核心将为SPORE的成员提供更大的机会，将调查结果转化为 白血病患者的治疗方案。 相关性（参见说明）： 该核心提供合成药物化学和结构生物学/计算化学方面的支持 将基础科学发现转化为小分子的设计和合成 用于假设检验的代理。具有治疗潜力的先导化合物将进一步经历结构上的变化。 优化以开发用于临床治疗的有效药物。

A major theme of this leukemia SPORE application is translational research that focuses on identifying therapeufically relevant targets for anti-leukemic drug discovery. Each of the projects presented in this application is a testament to a strong collaborative effort between clinicians and basic scientists, which nterfaces many aspects of translational research, including oncogenic signaling, epigenefics, experimental therapeufics, and immunology. The Medicinal Chemistry Core integrates the expertise of two laboratories, including medicinal chemistry, molecular and cell biology, and molecular pharmacology (Chen), and computational chemistry and structural biology (Li). In the past few years, this program has developed a series of agents targeting different molecular defects clinically relevant to leukemogenesis, two of which are ready to enter clinical trials in 2009. Thus, this core provides a platform to translate basic science findings from each of these projects into the design and synthesis of small-molecule agents for tesfing individual hypotheses, and adds an important dimension to expedite the translation from bench to the clinic. Specifically, the following three aims constitute the foci of this Medicinal Chemistry Core with initial emphasis on targefing immunomodulafion in tumor-specific T cells and natural killer cells (Project 3), and protein phosphatase (PP) 2A (Pilot Project 2), which will be expanded to address other new molecular targets arising from other projects. Overall, our specific aims include: Aim 1. To carry out lead opfimizafion of lenalidomidie to develop specific immunomodulatory drugs for chronic lymphocytic leukemia (CLL) therapy (in collaboration with Project 3). Aim 2. To carry out structural opfimization of FTY720 to develop novel PP2A-activating agents (in collaboration with Pilot Project 2). Aim 3. To provide aspects of medicinal chemistry service including custom synthesis, sample preparafions, computational chemistry, and structural biology to interested investigators of this SPORE application (all Projects) and other NCI SPORE and POl investigators. An example of this is providing OSU-HDAC42 to investigators in Projects 4, 5 and Developmental Project 1. Overall, this unique core will provide members of the SPORE a greater opportunity to translate findings into therapeutic opfions for patients with leukemia. RELEVANCE (See instructions): This Core provides support in synthetic medicinal chemistry and structural biology/computational chemistry to individual projects to translate basic science findings into the design and synthesis of small-molecule agents for hypothesis testing. Lead compounds with therapeutic potential will further undergo structural optimization to develop potent agents for clinical translafion.