Inhibiting the heat shock factor 1-regulated transcriptional program in cancer

描述(申请人提供)：在以前的工作中，我们已经证明了热休克因子1(HSF1)，哺乳动物热休克反应的主要调节因子，以一种强大的、多方面的方式发挥作用，使细胞培养和转基因小鼠发生恶性转化。与HSF1野生型小鼠相比，HSF1被敲除的转基因小鼠对各种致癌损伤导致的癌症的形成具有极大的抵抗力，这些致癌损伤包括RAS的激活突变和肿瘤抑制基因P53的热点突变。除了强调靶向HSF1的抗肿瘤活性外，小鼠对HSF1基因完全敲除的耐受性表明，HSF1的选择性抑制剂可能存在一个有用的治疗指标。不幸的是，目前还没有这样的小分子已知。因此，本项目的目标是开发HSF1的类药物抑制剂 在小鼠中具有有效和选择性活性的调节转录程序。我们假设，这些抑制物在探索这种古老的、高度保守的应激反应如何使细胞可能应对恶性肿瘤带来的问题方面将是无价的。它们还将以一种全新的作用模式为未来开发有用的抗癌药物提供有希望的线索。在之前的R-03拨款的支持下，我们最近通过NIH MLPCN计划完成了一项&GT；300,000种化合物高通量筛选(HTS)，该计划旨在识别HSF1的选择性抑制剂。我们最有希望的热门产品之一是天然产品罗格列胺A(ROCA)。为了从热门屏幕转向在动物身上具有强大和选择性活性的探针，已经与另一名领导附近化学方法学和图书馆开发(CMLD-BU)中心的研究人员建立了药物化学合作。他的团队已经从简单的材料开始，直接合成了不同的ROCA结构类似物。我们的共同专门知识和资源确保了在不依赖有限的自然资源的情况下为生物学研究提供充足的材料，并使我们能够进行初步的结构活性关系研究。这些已经确定了具有更强抗癌活性的化合物，但重大的靶标特异性问题和药理学责任仍有待解决。为了直接响应PAR-12-060的要求，我们建议进行“迭代生物测定和化学优化循环”，以将经过验证的HTS命中转变为有用的 体内化学探针。

DESCRIPTION (provided by applicant): In previous work we have demonstrated that Heat Shock Factor 1 (HSF1), master regulator of the mammalian heat shock response acts in a powerful, multi-faceted manner to enable malignant transformation both in cell culture and in transgenic mice. When compared to Hsf1 wild type mice, transgenic mice in which Hsf1 is knocked out are dramatically resistant to the formation of cancers driven by a variety of oncogenic lesions including activating mutations of RAS and hot-spot mutations of the tumor suppressor p53. In addition to highlighting the antitumor activity of targeting HSF1, the ability o mice to tolerate complete genetic knockout of HSF1 suggests that a useful therapeutic index is likely to exist for selective inhibitors of HSF1. Unfortunately, no such small molecules are currently known. Therefore, the goal of this project is to develop drug-like inhibitors of the HSF1 regulated transcriptional program with potent and selective activity in mice. We hypothesize that such inhibitors will be invaluable in probing how this ancient, highly conserved stress response makes it possible for cells to cope with the problems imposed by malignancy. They will also serve as promising leads for the future development of useful anticancer drugs with a completely new mode of action. Supported by a previous R-03 grant to one of the principal investigators on this project, we recently completed a >300,000 compound high throughput screen (HTS) through the NIH MLPCN program designed to identify selective inhibitors of HSF1. One of our most promising hits was the natural product rocaglamide A (RocA). To move from screen hit to a probe with potent and selective activity in animals, a medicinal chemistry collaboration has been established with another investigator who leads a nearby Chemical Methodology and Library Development (CMLD-BU) center. His group has achieved directed synthesis of diverse structural analogs of RocA starting from simple materials. Our joint expertise and resources ensure an adequate supply of material for biological studies independent of limited natural resources and have allowed us to pursue initial structure activity relationship (SAR) studies. These have identified compounds with more potent anticancer activity, but significant target-specificity issues and pharmacological liabilities remain to be addressed. In direct response to the mandate of PAR-12-060, we propose to undertake "iterative bioassay and chemical optimization cycles" to transition a validated HTS hit to a useful in vivo chemical probe.