Rational Design of Inhibitors of Polyamine Synthesis

项目描述（申请人提供）：本项目的总体目标是发现干扰多胺生物合成的新型抗癌药物。多胺是普遍存在的细胞组分，并且是正常细胞生长所必需的。在人体中，精胺和亚精胺是主要的多胺。先前的研究，包括大量的临床试验，表明抑制多胺生物合成是癌症化疗的有效靶点。在拟议的研究中，我们将集中在S-腺苷甲硫氨酸脱羧酶（ADMetDC），精胺/亚精胺N1-乙酰转移酶（SSAT）和多胺脱氢酶，亚精胺合酶和精胺合酶，作为基于结构的药物设计的目标。MetDC是多胺生物合成中的关键调节酶，并且该酶的水平响应于细胞周期而迅速变化。MGBG是第一个进入临床试验的MetDC抑制剂，显示出意想不到的毒性。最近，SAM486A的临床试验更加令人鼓舞。我们期待我们的基于结构的方法得到进一步的改进。SSAT催化多胺催化剂中的限速步骤。它是高度可诱导的，并且具有非常短的半衰期。细胞水平的SSAT增加的化合物，防止其降解。其中一些化合物在临床试验中显示出令人鼓舞的结果。亚精胺合酶和精胺合酶催化多胺生物合成的最后步骤。多胺脱氢酶的抑制剂尚未进入临床试验。在这个项目中，我们将使用三维结构和迭代的基于结构的药物设计来开发新的多胺生物合成抑制剂。该计划包括四个项目，生物化学（博士Pegg），晶体学（博士Ealick），建模（博士Guida）和合成（博士Secrist），和两个核心，行政和动物试验。行政核心将负责方案整合。一旦我们确定了有效的体外抑制剂，将在动物核心中对标准肿瘤模型进行进一步测试。一个具有临床肿瘤学专业知识的外部委员会将就项目优先事项和潜在的临床试验向我们提供建议。

DESCRIPTION (provided by applicant): The overall goal of this program project is to discover new cancer drugs that interfere with polyamine biosynthesis. Polyamines are ubiquitous cellular components and are necessary for normal cell growth. In humans, spermine and spermidine are the main polyamines. Previous studies, including numerous clinical trials, demonstrated that inhibition of polyamine biosynthesis is a valid target for cancer chemotherapy. In the proposed research, we will focus on S-adenosylmethionine decarboxylase (AdoMetDC), spermine/spermidine N1-acetyl transferase (SSAT) and the polyamine synthases, spermidine synthase and spermine synthase, as targets for structure-based drug design. AdoMetDC is a key regulatory enzyme in polyamine biosynthesis and levels of the enzyme vary rapidly in response to the cell cycle. The first AdoMetDC inhibitor to enter clinical trials, MGBG showed unexpected toxicity. More recently, clinical trials with SAM486A have been much more encouraging. We expect even further improvements with our structure-based approach. SSAT catalyzes the rate-limiting step in polyamine catabolism. It is highly inducible and has a very short half-life. Cellular levels of SSAT are increased by compounds that prevent its degradation. Some of these compounds have shown encouraging results in clinical trials. Spermidine synthase and permine synthase catalyze the final steps of polyamine biosynthesis. Inhibitors of the polyamine synthases have not yet entered clinical trials. In this program we will use the 3-D structures and iterative structure-based drug design to develop novel inhibitors of polyamine biosynthesis. The program consists of four projects, biochemistry (Dr. Pegg), crystallography (Dr. Ealick), modeling (Dr. Guida), and synthesis (Dr. Secrist), and two cores, administrative and animal testing. The administrative core will be responsible for program integration. Once we have identified potent in vitro inhibitors, further testing against standard tumor models will be carried out in the animal core. An external committee with expertise in clinical oncology will advise us on project priorities and potential clinical trials.