STRUCTURAL STUDIES ON NATURAL PRODUCT LEADS FOR RESTORATION OF P53 FUNCTION

天然产物的结构研究有助于恢复 P53 功能

• 批准号: 2339246
• 金额: --
• 依托单位: PHARMAGENICS, INC.
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/2339246
• 关键词: X ray crystallography; antineoplastics; biological products; chemical structure function; gene expression; gene mutation; nucleic acid structure; oncogenes; pharmacokinetics; plant extracts; structural biology; tumor suppressor genes

The goal of the NCNPDD group is to target the p53 tumor suppressor system int he screening of natural compound libraries in an attempt to identify compounds that restore the activity of p53 in tumor cells. Recent rapid advances in cancer research have identified the p53 tumor suppressor system as the body-s forefront defense against cancer. p53 is the most frequently mutated gene identified in human cancers. Mutations occur in over 50 percent of all cancer cases, and many of the remaining cases involve cellular or viral oncogenes that inactivate the p53 protein. The cellular and biochemical mechanisms mediating p53's tumor suppressing effects have recently been elucidated. At the cell biological level, p53 can induce cell cycle arrest and programmed cell death in response to DNA damage or inappropriate growth signals. At the biochemical level, p53 can bind to specific DNA sequences and activate the transcription of genes. Tumor derived p53 mutants are defective in DNA binding, and consequently they cannot induce cell cycle arrest or apoptosis. In addition to the cellular and biochemical mechanisms, the recent determination of the crystal structure of a p53-DNA complex by this laboratory has also elucidated the structural basis of p53 function. To further address issues pertaining to p53's inactivation by mutations in tumors, systematic biochemical, biophysical, and crystallographic studies of a large set of tumor derived p53 mutants will be undertaken as part of this laboratory program. The mechanism based differences between wild type and mutant p53, and in particular biochemical and structural differences, will be explored in the rational design of natural product screens in attempt to identify compounds that restore function to tumor derived p53 mutants. Lead compounds emerging from the screens will be co-crystallized in order to determine their mechanism of action, and to aid in their development into useful therapeutic agents. Structural studies will be extended to (i) the MDM2 oncogene which is p53's natural inhibitor and has been found amplified in certain tumors, and (ii) the Cip1/WAF1-cyclin-cdk complex which appears to mediate p53's growth inhibitory effects. Emphasis will be on determining their structural mechanisms of action of MDM2 and of Cip1/WAF1 to aid in the rational design of model systems to be used in the screening efforts. Lead compounds emerging from the screens will be co-crystallized in complex with their target proteins to facilitate their development into useful therapeutic agents.

NCNPDD组的目标是靶向p53肿瘤抑制系统 对天然化合物库进行筛选， 在肿瘤细胞中恢复p53活性的化合物。近期快速 癌症研究的进展已经确定了p53肿瘤抑制系统 作为身体对抗癌症的最前沿防御。p53最常见 在人类癌症中发现的突变基因。突变发生在50多个 所有癌症病例的10%，其余的许多病例涉及 与p53蛋白结合的细胞或病毒癌基因。蜂窝 介导p53肿瘤抑制作用的生化机制 最近得到了澄清。在细胞生物学水平上，p53可以诱导 细胞周期停滞和程序性细胞死亡，以响应DNA损伤，或 不适当的增长信号。在生物化学水平上，p53可以结合到 特定的DNA序列并激活基因的转录。肿瘤 衍生的p53突变体在DNA结合方面有缺陷，因此它们 不能诱导细胞周期停滞或凋亡。除了蜂窝之外 和生化机制，最近确定的晶体 该实验室的p53-DNA复合物的结构也阐明了 p53功能的结构基础。进一步处理与下列方面有关的问题： 肿瘤中突变导致的p53失活，系统生化， 生物物理学和晶体学研究的一个大的肿瘤来源的 p53突变体将作为该实验室计划的一部分进行。的 野生型和突变型p53之间基于机制的差异， 特别是生物化学和结构差异，将在 天然产物筛选的合理设计，以尝试识别化合物 恢复肿瘤来源的p53突变体的功能。先导化合物 从屏幕上出现的将被共结晶，以确定 他们的行动机制，并帮助他们的发展成为有用的 治疗剂。结构研究将扩展到（i）MDM 2 癌基因是p53的天然抑制剂， 某些肿瘤，和（ii）Cip 1/WAF 1-细胞周期蛋白-cdk复合物， 介导p53的生长抑制作用。重点将是确定 MDM 2和Cip 1/WAF 1的结构作用机制有助于 合理设计用于筛选工作的模型系统。 铅化合物从屏幕上出现将共结晶在复杂的 与它们的靶蛋白结合，以促进它们的发展， 治疗剂。