Identifying the Molecular Targets of Novel Cytotoxic Agents

天然进化而来抑制细胞生长的化合物已被证明在癌症研究和治疗中具有非常重要的价值 心理治疗。它们经常有效地发挥作用，特别是--使它们成为有用的信号探针 小路。最近的例子包括组蛋白去乙酰酶抑制剂曲波新，免疫抑制剂 雷帕霉素和Sonic Hedgehog信号抑制剂环丙胺。这个项目的目标是确定 几种新天然产品的目标和作用模式--我们认为这些产品具有类似的潜力 推动与人类癌症相关的新的细胞生物学研究。这些化合物也代表了铅结构 新疗法的发展。结合经典遗传学的多管齐下的方法，反向 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 继续对已发现的抗有丝分裂素耐药新机制的遗传学研究 半腹股沟。这与HTI-286的高级临床状态有关，HTI-286是一种半固醇素衍生物 目前正在进行第二阶段的人体试验。我们还建议确定天然产物psymberin的靶点， 最近报道在NCI开发治疗的体外实验中显示出不同的细胞毒性 筛选方案。我们已经实现了这一天然产物的实用全合成，这使得 获得用于行动模式研究的合成变种。我们已经证明psymberin对 线虫线虫-基因筛选的基础，以识别抗药性突变体。帕劳阿蒙是一种罕见的 来自海洋的天然产物，具有免疫抑制和抗增殖活性。它的合成是 接近完成和类似的方法(遗传和生化)将被用来剖析它的模式-- 行动。最后，我们将探讨细胞毒素卤素的作用模式，卤素是一种被证明可以抑制 DNA甲基转移酶I酶。 与公共卫生相关：FDA批准的抗癌药物中有很大一部分，还有更多 发展是基于天然的产品领先地位。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.