Hsp90s as targets in the development of anticancer drugs

描述：(申请人提供) HSP90家族蛋白由Hsp90α和β、Grp94和 陷阱-1。它们是丰富的伴侣蛋白，在蛋白质中发挥作用 重折叠加工与几个键的构象成熟 信号蛋白，包括类固醇受体、Raf激酶和几个 跨膜酪氨酸激酶。热休克蛋白90在肿瘤中过表达，并可能在肿瘤中发挥作用 稳定信号在维持转化表型中的作用 蛋白质和突变的原癌基因及其介导的肿瘤细胞存活 低氧，恶劣的环境。 安山霉素抗生素和自由基是天然产物，可与 在HSP90家族蛋白中保守的口袋。该口袋的占有率为 药物改变了它们的功能，导致信号的退化 需要Hsp90的蛋白质。向癌细胞中添加阿萨米星会导致 依赖Rb的G1期停滞、分化和细胞凋亡。有缺陷的电池 Rb功能停滞于早中期，并发生细胞凋亡。一种阿萨霉素，17-烯丙基氨基格尔德纳霉素(17-AAG)目前正在进行临床试验。 这项研究的主要目标是确定与铅结合的化合物 与HSP90结合并具有选择性活性的化合物 授予新奇的猥亵属性。 一种先导化合物，格尔达霉素(GM)二聚体已被鉴定为 HER家族酪氨酸激酶的选择性。我们也已经开始合成 旨在结合HSP90家族口袋并开发化学物质的化合物 与不同的HSP90家族成员结合的分子库。这些 将对分子进行筛选，以确定其选择性结合到 伴侣，降解特定靶点，并抑制肿瘤细胞与特定的 分子损伤。我们的目标是衍生出选择性化合物，并用它们来 确定抑制HSP90家族每个成员的生物学效应 并确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.