Identifying the Molecular Targets of Novel Cytotoxic Agents

已经证明，自然进化出的抑制细胞生长的化合物在癌症研究中是无价的， 疗法它们通常发挥其有效和特异性的作用，使它们成为有用的信号探针 途径。最近的例子包括组蛋白去乙酰化酶抑制剂trapoxin， 雷帕霉素和Sonic Hedgehog信号传导抑制剂环巴胺。这个项目的目标是确定 the target目标and mode模式of action行动for several新natural自然products产品--one we believe have similar类似potential潜力to 推动与人类癌症相关的新细胞生物学研究。这些化合物还代表了用于以下的先导结构： 新疗法的发展。一种多管齐下的方法，结合了经典遗传学、反向遗传学、 遗传学、化学、细胞生物学和生物化学将用于这些目的。具体来说，我们建议 继续进行抗有丝分裂药物发现的新耐药机制的遗传研究， 半海星素这与HTI-286（一种哈米特林衍生物）的高级临床状态有关 目前处于第二阶段人体试验中。我们还提出鉴定天然产物psymberin的靶标， 最近有报道称其在NCI体外发育治疗中显示出不同的细胞毒性 筛选程序。我们已经实现了这种天然产物的实际全合成， 获得用于作用模式研究的合成变体。我们已经证明了Psymberin对 线虫C elegans-遗传筛选的基础，以确定抗性突变体。帕劳的阿木尼是一种罕见的 来自海洋的具有免疫抑制和抗增殖活性的天然产物。其合成 接近完成和类似的方法（遗传和生物化学）将被应用于解剖其模式- 行动上最后，我们将探讨细胞毒素卤代龙的作用模式，这种分子被证明可以抑制细胞内的 DMA甲基转移酶I酶。 与公共卫生的相关性：FDA批准的抗癌药物中有很大一部分， 开发是基于天然产品的铅。这项研究将调查新的天然产品， 通过独特的机制来抑制人类癌细胞的生长。

Compounds that have evolved naturally to inhibit cell growth have proven invaluable in cancer research and therapy. They often exert their effects potently andspecifically - making them useful probes of signaling pathways. Recent examples include the histone deacetylase inhibitor trapoxin, the immunosuppressant rapamycin, and the Sonic Hedgehog signaling inhibitor cyclopamine. The goal of this project is to determine the targets and mode-of-actionfor several newnatural products - ones we believe have similar potential to drive new cell biology research relevant to human cancer. The compounds also represent lead structures for the development of novel therapeutics. A multi-pronged approach combining classical genetics, reverse genetics, chemistry, cell biology, and biochemistry will be used for these purposes. Specifically, we propose to continue genetic studies of a new mechanism of drug resistance uncovered with the anti-mitotiic hemiasterlin. This is relevant in light of the advanced clinical status of HTI-286, a hemiasterlin derivative currently in Phase II human trials. We also propose to identify the target of the natural product psymberin, which was recently reported to display differential cytotoxicity in the NCI Developmental Therapeutics in Vitro Screening Program.We have achieved a practical total synthesis of this natural product, which allows access to synthetic variants for mode-of-action studies. We have shown psymberin is highly toxic to the nematode C elegans-a basis for genetic screens to identify resistant mutants. Palau'amlne is a rare natural product from the ocean having immunosuppressive and antiproliferative activities. Its synthesis is near completion and similar approaches (genetic and biochemical) will be applied to dissect its mode-of- action. Finally, we will pursue the mode-of-action of the cytotoxin halomon, a molecule shown to inhibit the DMA methyltransferase I enzyme. Relevance to public health: A large fraction of FDAapproved anticancer drugs and many more in development are based upon natural product leads. This research will investigate new natural products that operate by unique mechanisms to inhibit human cancer cell growth.