Development and Evaluation of Purine and Coumarin Based Hsp90 Inhibitors

描述(申请人提供)：90 kDa热休克蛋白被证明是非同寻常的癌症化疗靶点，这一事实证明，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-末端抑制剂，主要是格尔达霉素衍生的，这些化合物表现出严重的配方、程序和剂量困难，因为这些化合物在诱导客户蛋白质降解的同时诱导HSP。Neck和他的同事之前的研究确定Hsp90含有一个C-末端的ATP结合位点，它与香豆素抗生素竞争结合而不是ATP。与N末端抑制剂一样，C末端结合域的抑制剂也会导致肿瘤细胞生长和增殖所需的依赖于Hsp90的客户蛋白的降解。香豆素抗生素的一个主要缺点是它们与Hsp90的结合很弱(IC50约为700微摩尔)；然而，我们团队最近的研究导致化合物的活性是这些天然产品的1000倍。通过对C末端结合位点的广泛研究和阐明，我们已经了解到如何以以前没有意识到的方式调控Hsp90。因此，我们开发了在低浓度下诱导HSP的化合物，使变性蛋白重新折叠，作为治疗各种神经退行性疾病的新方法。相反，我们已经构建了在不诱导HSP的情况下抑制HSP90的分子，因此提供了一种机制，通过该机制可以绕过临床上观察到的N末端抑制剂的困难。在这一应用中，我们建议基于我们最近阐明的C末端结合位点来开发抗癌药物，以努力生产适合临床评估的药物。此外，我们计划在其他体内癌症模型中研究最活跃的化合物

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