Identifying the Molecular Targets of Novel Cytotoxic Agents

识别新型细胞毒剂的分子靶点

• 批准号: 7315650
• 负责人: JEF KAREL DE BRABANDER
• 金额: $ 85.44万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-24 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7315650
• 关键词: 6-bromo-3-(bromomethyl)-7-methyl-2,3,7-trichloro-1-octene; Affinity Chromatography; Animals; Antimitotic Agents; Antineoplastic Agents; Binding; Biochemical; Biochemical Genetics; Biochemistry; Biological; Biological Factors; Caenorhabditis elegans; Cancer Cell Growth; Cells; Cellular biology; Chemicals; Chemistry; Class; Clinical; Collaborations; Complex; Cytotoxic agent; Cytotoxin; DMA-methyltransferase; DNA Methyltransferase; DNA Modification Methylases; Development; Developmental Therapeutics Program; Drug resistance; Enzymes; Gene Mutation; Genes; Genetic; Genetic Screening; Goals; HTI-286; Histone Deacetylase Inhibitor; Human; Immunosuppressive Agents; In Vitro; Laboratories; Lead; Libraries; Light; Malignant Neoplasms; Mammalian Cell; Marines; Missense Mutation; Molecular; Molecular Target; Multi-Drug Resistance; Mutation; Nematoda; Oceans; Palau; Palau' amine; Pharmaceutical Preparations; Pharmacology; Phase; Proteins; Public Health; Purpose; Radiolabeled; Reagent; Reporting; Research; Research Personnel; Resistance; Role; Screening procedure; Signal Pathway; Sirolimus; Structure; Toxin; Trapoxin; Tubulin; Variant; analog; anticancer research; base; cell growth; cyclopamine; cytotoxicity; drug sensitivity; gain of function; hemiasterlin; high throughput screening; in vivo; inhibitor/antagonist; interest; killings; loss of function; mRNA Differential Displays; mutant; novel; novel therapeutics; positional cloning; programs; prohibitin; radiotracer; research study; resistance mechanism; scaffold; smoothened signaling pathway

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.

自然进化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无价的价值。 治疗。它们经常有效且特异性地发挥作用——使它们成为有用的信号传导探针 途径。最近的例子包括组蛋白脱乙酰酶抑制剂 Trapoxin、免疫抑制剂 雷帕霉素和 Sonic Hedgehog 信号抑制剂环巴明。该项目的目标是确定 几种新天然产品的目标和作用方式 - 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细胞生物学研究。这些化合物还代表了先导结构 新疗法的开发。结合经典遗传学、反向遗传学的多管齐下的方法 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 继续对抗有丝分裂药物发现的新耐药机制进行遗传学研究 半斯特林。鉴于 HTI-286（一种半斯特林衍生物）的高级临床状态，这是相关的 目前正在进行 II 期人体试验。我们还建议确定天然产物 psymberin 的靶标， 最近有报道称其在 NCI 体外开发治疗中显示出不同的细胞毒性 筛选计划。我们已经实现了这种天然产物的实用全合成，这使得 获得用于作用模式研究的合成变体。我们已经证明 psymberin 对人体有剧毒 线虫秀丽隐杆线虫 - 鉴定抗性突变体的遗传筛选的基础。帕劳阿姆内是一个罕见的 来自海洋的天然产物，具有免疫抑制和抗增殖活性。其合成为 即将完成，类似的方法（遗传和生物化学）将被应用于剖析其模式 行动。最后，我们将探究细胞毒素 halomon 的作用模式，该分子被证明可以抑制 DMA 甲基转移酶 I。 与公共卫生的相关性： FDA 批准的大部分抗癌药物以及许多其他药物 开发基于天然产品先导。这项研究将调查新的天然产物 通过独特的机制来抑制人类癌细胞的生长。