Hsp90s as targets in the development of anticancer drugs

描述：（申请人提供） hsp 90蛋白家族由Hsp 90 α和β、Grp 94和Hsp 95组成。 陷阱一号它们是丰富的分子伴侣蛋白，在蛋白质中发挥作用， 重折叠和加工以及几个关键的构象成熟 信号蛋白，包括类固醇受体，Raf激酶和几种 跨膜酪氨酸激酶。Hsp 90在肿瘤中过表达，可能与肿瘤的发生发展有关。 通过稳定信号传导维持转化表型的作用 蛋白质和突变的原癌基因，并通过介导肿瘤细胞存活， 缺氧恶劣的环境 安莎霉素抗生素和根赤霉素是天然产物， HSP 90家族蛋白中的保守口袋。占据这个口袋， 药物改变了它们的功能，并导致信号转导的降解。 需要Hsp 90的蛋白质。在癌细胞中添加安莎霉素会导致 RB依赖性G1期阻滞、分化和凋亡。缺陷细胞 RB功能阻滞于前中期，发生凋亡。安莎霉素的一种，17 -烯丙基氨基格尔德霉素（17- AAG）目前正在临床试验中。 这项研究的主要目标是确定结合铅的化合物 结合HSP 90口袋并具有选择活性的化合物 赋予新的不雅性质。 一种先导化合物，格尔德霉素（GM）二聚体已被鉴定为 HER家族酪氨酸激酶的选择性。我们也开始合成 设计用于结合hsp 90家族口袋并产生化学活性的化合物 结合不同hsp 90家族成员的分子库。这些 分子将被筛选，以确定它们选择性地结合到 分子伴侣，降解特定的靶标，并抑制肿瘤细胞， 分子损伤我们的目标是获得有选择性的化合物， 确定抑制每种HSP 90家族成员的生物学效应 并鉴定具有抗癌活性的新的靶向药物。

DESCRIPTION: (Provided by Applicant) The hsp90 family of proteins consists of Hsp90 alpha and beta, Grp94 and Trap-1. They are abundant chaperone proteins that play roles in protein refolding and processing and the conformational maturation of several key signaling proteins, including steroid receptors, Raf kinase and several transmembrane tyrosine kinases. Hsp90 is overexpressed in tumors and may play a role in maintaining the transformed phenotype by stabilizing signaling proteins and mutated protooncogenes and by mediating tumor cell survival in hypoxic, harsh environments. Ansamycin antibiotics and radicicol are natural products that bind to a conserved pocket in the hsp90 family proteins. Occupancy of this pocket by drug alters their function and causes the degradation of the signaling proteins that require Hsp90. Addition of ansamycins to cancer cells causes RB-dependent G1 arrest, differentiation and apoptosis. Cells with defective RB function arrest in prometaphase and undergo apoptosis. One ansamycin, 17 -allylaminogeeldanamycin (17- AAG) is currently in clinical trial. The main goal of this research is to identify compounds that bind lead compounds that bind to the hsp90 pocket and have selective activities that confer novel indecence properties. A lead compound, a geldanamycin (GM) dimer has been identified with selectivity for HER-family tyrosine kinases. We have also begun to synthesize compounds designed to bind to the hsp90-family pocket and to develop chemical libraries of molecules that bind to the different hsp90 family members. These molecules will be screened for their ability to bind selectively to the chaperones, degrade specific targets, and inhibit tumor cells with particular molecular lesions. Our goal is to derive selective compounds and use them to determine the biologic effects of inhibiting each of the hsp90 family members and to identify new, target-directed drugs with anticancer activity.