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Development and Evaluation of Purine and Coumarin Based Hsp90 Inhibitors`

基于嘌呤和香豆素的 Hsp90 抑制剂的开发和评价

基本信息

批准号：
7079122
负责人：
Brian S J Blagg
金额：
$ 25.56万
依托单位：
UNIVERSITY OF KANSAS LAWRENCE
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-05-19 至 2009-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7079122
关键词：
analog clinical trials lead neoplasm /cancer nucleotides protein folding proteins purines

项目摘要

DESCRIPTION (provided by applicant): The 90 kDa heat shock proteins are proving to be extraordinary cancer chemotherapeutic targets as evidenced by the fact that 26 clinical trials are currently in progress. Unfortunately, all of these trials are based upon the N-terminal inhibitor, geldanamycin, which has serious formulation difficulties and produces toxicity unrelated to Hsp90 inhibition by virtue of its redox-active and electrophilic quinone ring. Only one total synthesis of this molecule has been reported, and the overall yield was 0.017% after 43 steps, suggesting that the preparation of analogues would be difficult. More recently, Neckers and coworkers determined that Hsp90 contains a C-terminal ATP binding site that bound coumarin antibiotics competitively versus ATP. Like N-terminal inhibitors, inhibitors of the C-terminal binding domain also cause the degradation of Hsp90-dependent client proteins involved in tumor cell growth and proliferation. A major drawback of the coumarin antibiotics is that they bind weakly to Hsp90 (IC50 approximately 700 micromolar); however, they remain the most potent C-terminal inhibitors described in the literature. We have recently identified a compound that is 700-7000 x's more active than the coumarin antibiotic in collaboration with Len Neckers and Jeff Holzbeierlein. This molecule has been evaluated in several tumor cell lines and has potent activity against a wide range of Hsp90 client proteins. In an effort to increase the potency of our lead molecule, we have proposed to incorporate functionalities that exist in the nucleotide specific substrates onto our lead compound to afford additional interactions with the Hsp90 C-terminal binding site. In addition, we propose to evaluate our lead compound in murine xenograft models of prostate cancer. Finally, it is proposed that by compromising the Hsp90 protein folding machinery with low doses of our lead compound, or any improved analogue, it will provide an acceptable concentration of other clinically used anti-tumor agents to induce apoptosis without detrimental side effects. As a consequence of these studies, we believe we can provide a basis upon which new inhibitors of the Hsp90 protein folding process can be developed without the deleterious side effects of the geldanamycin derivatives that are currently plagued in clinical trials.

描述（由申请人提供）：事实证明，90 kDa热休克蛋白是非凡的癌症化疗靶点，目前正在进行26项临床试验就证明了这一点。不幸的是，所有这些试验都是基于N-末端抑制剂格尔德霉素，其具有严重的配制困难，并且由于其氧化还原活性和亲电子醌环而产生与Hsp 90抑制无关的毒性。该化合物的全合成只有一次报道，经过43步反应，总收率为0.017%，这表明类似物的制备将是困难的。最近，Neckers及其同事确定Hsp 90含有C末端ATP结合位点，其与香豆素抗生素竞争性结合ATP。与N-末端抑制剂一样，C-末端结合结构域的抑制剂也引起参与肿瘤细胞生长和增殖的Hsp 90依赖性客户蛋白的降解。香豆素类抗生素的一个主要缺点是它们与Hsp 90的结合较弱（IC 50约为700微摩尔）;然而，它们仍然是文献中描述的最有效的C-末端抑制剂。我们最近与Len Neckers和Jeff Holzbeierlein合作，发现了一种比香豆素抗生素活性高700-7000倍的化合物。该分子已在几种肿瘤细胞系中进行了评估，并对广泛的Hsp 90客户蛋白具有有效的活性。为了提高我们的先导分子的效力，我们已经提出将存在于核苷酸特异性底物中的功能性并入我们的先导化合物上，以提供与Hsp 90 C-末端结合位点的额外相互作用。此外，我们建议在前列腺癌的小鼠异种移植模型中评估我们的先导化合物。最后，提出通过用低剂量的我们的先导化合物或任何改进的类似物损害Hsp 90蛋白折叠机制，将提供可接受浓度的其他临床使用的抗肿瘤剂以诱导细胞凋亡而没有有害的副作用。作为这些研究的结果，我们相信我们可以提供一个基础，在此基础上，可以开发新的抑制剂的Hsp 90蛋白折叠过程中没有有害的副作用格尔德霉素衍生物，目前困扰在临床试验。