Inhibitors of Heat Shock Response

描述(申请人提供)：抗癌药物的最新发展导致分离出几种有效的结构性热休克反应(HSR)阻滞剂，如HSP90抑制剂格尔达那霉素(DMAG)和蛋白酶体抑制剂VELCADE(Bortezomib)，这对多种类型的癌细胞的生存至关重要。我们在动物模型中的初步研究结果表明，不幸的是，涉及这些药物本身的治疗并不能诱导肿瘤中特异性和有效的细胞死亡，因为它们诱导了额外的HSF-1依赖的信号通路。然而，PTS诱导剂DMAG和Bortezomib与抑制HSF-1介导的转录的化合物协同作用，诱导高达50倍的肿瘤细胞死亡。 拟议计划的最终目标是开发一种新型的高潜力抗癌药物，既针对基础的又针对诱导的HSR。第一阶段研究将通过高通量筛选(HTS)一个已知药物的小型资料库来启动药物开发管道，并证明拟议的抗癌疗法的价值。第二阶段研究的主要目标将是开发和启动针对可诱导HSR的几种先导化合物的临床前研究。 我们的目标是分离出一种新型的抗癌药物，这种药物具有独特的性质，在文献中没有描述，也没有应用于临床试验。通过这种方式，我们的方法可能会发现具有巨大治疗潜力的药物，这些药物可以显著提高抗癌化疗的效率。 公共卫生相关性：该项目的目标是分离能够抑制癌症特异性热休克反应通路的化合物，从而建立新的抗肿瘤治疗方法。热休克反应的抑制剂将通过使用一组含有特定热休克报告基因的癌细胞株从具有药理学特征的化合物库中分离出来，从而允许开发基于细胞的读出药物筛选方案和分离新的有效的抗肿瘤药物。

DESCRIPTION (provided by applicant): The recent development of anti-cancer pharmaceuticals has resulted in the isolation of several effective blockers of constitutive heat shock response (HSR), such as the HSP90 inhibitor Geldanamycin (DMAG) and the proteasome inhibitor Velcade (Bortezomib), which is critical to the survival of a wide range of cancer cell types. The results of our preliminary studies in an animal model show that unfortunately, treatment involving these drugs by themselves does not induce specific and efficient cell death in tumors, because they induce an additional HSF-1-dependent signaling pathway. However, the PTS inducers DMAG and Bortezomib act synergistically with chemical compounds that suppress HSF-1-mediated transcription to induce up to a 50-fold more tumor cell death. The ultimate goal of the proposed program is to develop a novel class of highly potential anti-cancer drugs that target both basal and inducible HSR. Phase I studies will initiate the drug development pipeline by high-throughput screening (HTS) of a small library of known pharmaceuticals and prove the value of the proposed anti-cancer therapy. The main goal of Phase II studies will be to develop and initiate preclinical studies of several lead compounds targeting inducible HSR. We aim to isolate a novel class of anti-cancer drugs that has unique properties and that has not been described in the literature or applied in clinical trials. In this way, our approach may identify drugs with tremendous therapeutic potential that could significantly improve the efficiency of anti-cancer chemotherapy. PUBLIC HEALTH RELEVANCE: The goal of this project is to isolate chemical compounds capable of suppressing cancerspecific heat shock response pathways leading to establishment of novel approaches to anti-tumor therapies. Inhibitors of heat shock response will be isolated from a library of pharmaceutically characterized compounds by using a panel of cancer cell lines containing a specific heat shock reporter gene, allowing for the development of cellbased readout drug screening protocols and isolation of new potent anti-tumor drugs.