Rational Design of Inhibitors of Polyamine Synthesis

描述(申请人提供)：该计划项目的总体目标是发现干扰多胺生物合成的新的抗癌药物。多胺是普遍存在的细胞成分，是细胞正常生长所必需的。在人类中，精胺和亚精胺是主要的多胺。以往的研究，包括大量的临床试验，表明抑制多胺的生物合成是癌症化疗的有效靶点。在拟议的研究中，我们将重点关注S-腺苷蛋氨酸脱羧酶(ADO-MetDC)、精胺/亚精胺N1-乙酰转移酶(SSAT)以及多胺合成酶-亚精胺合酶和精胺合酶，作为基于结构的药物设计的靶点。ADOMetDC是多胺生物合成的关键调节酶，该酶的水平随着细胞周期的变化而迅速变化。作为第一个进入临床试验的Adobe MetDC抑制剂，MGBG显示出意想不到的毒性。最近，SAM486A的临床试验更令人鼓舞。我们预计我们的基于结构的方法会有进一步的改进。SSAT催化多胺分解代谢的限速步骤。它的诱导性很强，半衰期很短。防止SSAT降解的化合物会增加细胞中SSAT的水平。其中一些化合物在临床试验中显示出令人鼓舞的结果。亚精胺合酶和多胺合酶催化多胺生物合成的最后几步。多胺合成酶的抑制剂还没有进入临床试验。在这个项目中，我们将利用三维结构和基于迭代结构的药物设计来开发新型的多胺生物合成抑制剂。该计划包括四个项目，生物化学(Pegg博士)、结晶学(Ealick博士)、建模(Guida博士)和合成(Secrist博士)，以及行政和动物试验两个核心。行政核心将负责项目整合。一旦我们确定了有效的体外抑制物，将在动物核心进行针对标准肿瘤模型的进一步测试。一个在临床肿瘤学方面具有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.