Development and Evaluation of Purine and Coumarin Based Hsp90 Inhibitors

描述（由申请人提供）：90 kDa热休克蛋白被证明是非凡的癌症化疗靶点，目前有20多项临床试验正在进行中。不幸的是，所有这些试验都是基于n端抑制剂，主要是格尔达霉素衍生的，由于这些化合物在诱导客户蛋白降解的浓度相同的情况下诱导热休克蛋白，因此在配方、计划和剂量方面存在严重困难。Neckers及其同事先前的研究确定，Hsp90含有c端ATP结合位点，可与香豆素抗生素竞争性地结合ATP。与n端抑制剂一样，c端结合域的抑制剂也会导致肿瘤细胞生长和增殖所需的hsp90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Hsp90结合较弱（IC50约为700微摩尔）；然而，我们小组最近的研究发现，这些化合物的活性是这些天然产物的1000倍。通过对C末端结合位点的广泛研究和阐明，我们了解了如何以以前未实现的方式调节Hsp90。因此，我们已经开发出低浓度诱导热休克蛋白的化合物，以重新折叠变性蛋白，作为治疗各种神经退行性疾病的新方法。相比之下，我们已经构建了抑制Hsp90而不诱导Hsp的分子，因此提供了一种机制，通过这种机制可以绕过临床中N端抑制剂所观察到的困难。在这个应用中，我们建议基于我们最近阐明的c末端结合位点开发抗癌药物，以生产适合临床评价的药物。此外，我们计划在其他体内癌症模型中研究最有效的化合物

DESCRIPTION (provided by applicant): The 90 kDa heat shock proteins are proving to be extraordinary cancer chemotherapeutic targets as evidenced by the fact that more than 20 clinical trials are currently in progress. Unfortunately, all of these trials are based upon N-terminal inhibitors, primarily geldanamycin- derived, which exhibit serious formulation, scheduling and dosing difficulties as these compounds induce Hsp's at the same concentration they induce client protein degradation. Previous studies by 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 required for tumor cell growth and proliferation. A major drawback of the coumarin antibiotics is that they bind weakly to Hsp90 (IC50 approximately 700 micromolar); however, recent studies by our group have led to compounds >1000 fold more active than these natural products. Through extensive studies and elucidation of the C- terminal binding site, we have learned how to modulate Hsp90 in ways not previously realized. Thus, we have developed compounds that induce Hsp's at low concentrations that refold denatured proteins as a new method to treat various neurodegenerative diseases. In contrast, we have constructed molecules that inhibit Hsp90 without inducing Hsp's, and therefore provide a mechanism by which to bypass difficulties observed with N- terminal inhibitors in the clinic. In this application we propose to develop anticancer agents based on our recently elucidated C-terminal binding site in an effort to produce agents suitable for clinical evaluation. In addition, we plan to investigate the most active compounds in additional in vivo models of cancer PUBLIC HEALTH RELEVANCE: Current Hsp90 inhibitors in clinical trials exhibit detrimental properties that are proving difficult to overcome. We have identified molecules that do not exhibit these deleterious properties and have proven to be exceptional in preliminary animal models of cancer. Therefore, the goal of this proposal is to attack multiple cancer-enabling enzymes by inhibiting Hsp90 at a new location and to produce new clinical candidates for the treatment of cancer