STRUCTURAL STUDIES ON NATURAL PRODUCT LEADS FOR RESTORATION OF P53 FUNCTION

NCNPDD小组的目标是针对p53肿瘤抑制系统 筛选天然化合物文库，试图鉴定 恢复肿瘤细胞中P53活性的化合物。最近的快速 癌症研究的进展已经确定了p53肿瘤抑制系统 身为S抗癌一线的防御工事。P53是最常见的 在人类癌症中发现的突变基因。突变发生在50岁以上 %的癌症病例，其余许多病例涉及 使P53蛋白失活的细胞或病毒癌基因。蜂窝手机 而介导P53‘S抑瘤作用的生化机制有 最近才被阐明。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是对DNA损伤或 不适当的增长信号。在生化水平上，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结合方面存在缺陷，因此它们 不能诱导细胞周期停滞或凋亡。除了蜂窝网络 和生化机制，最近对晶体的测定 本实验室的P53-DNA复合体的结构也阐明了 P53功能的结构基础。进一步解决与以下方面有关的问题 肿瘤中突变导致的P53‘S失活，系统生化， 一大批肿瘤来源的生物物理和结晶学研究 作为这一实验室计划的一部分，将进行p53突变。这个 野生型和突变型P53在机制上的差异 特殊的生化和结构差异，将在 天然产物筛的合理设计试图鉴定化合物 恢复肿瘤来源的P53突变体的功能。先导化合物 从屏幕上显现出来的东西将被共结晶，以确定 他们的行动机制，并帮助他们发展成为有用的 治疗剂。结构研究将扩展到(I)MDM2 已发现扩增的癌基因是P53‘S天然抑制物 某些肿瘤，以及(Ii)Cip1/WAF1-Cyclin-cdk复合体 介导P53‘S的生长抑制作用。重点将放在确定 MDM2和Cip1/WAF1的结构作用机制 合理设计用于筛选工作的模型系统。 从屏幕上出现的铅化合物将以络合物的形式共结晶 与它们的目标蛋白一起促进它们的发展成为有用的 治疗剂。

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.