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

描述（由申请人提供）：在之前的工作中，我们已经证明，哺乳动物热休克反应的主要调节因子热休克因子1（HSF1）以强大的、多方面的方式发挥作用，使细胞培养物和转基因小鼠中的恶性转化成为可能。与 Hsf1 野生型小鼠相比，Hsf1 被敲除的转基因小鼠对各种致癌病变（包括 RAS 激活突变和肿瘤抑制因子 p53 的热点突变）驱动的癌症形成具有显着的抵抗力。除了强调针对HSF1的抗肿瘤活性之外，小鼠耐受HSF1完全基因敲除的能力表明HSF1的选择性抑制剂可能存在有用的治疗指数。不幸的是，目前尚不知道这样的小分子。因此，该项目的目标是开发HSF1的药物样抑制剂 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，此类抑制剂对于探索这种古老的、高度保守的应激反应如何使细胞能够应对恶性肿瘤带来的问题具有不可估量的价值。它们还将为未来开发具有全新作用模式的有用抗癌药物提供有前景的线索。在之前向该项目的一位主要研究人员提供的 R-03 资助的支持下，我们最近通过 NIH MLPCN 计划完成了超过 300,000 种化合物的高通量筛选 (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卡酰胺 A (RocA)。为了从屏幕点击转向在动物中具有有效和选择性活性的探针，我们与另一位领导附近化学方法和图书馆开发 (CMLD-BU) 中心的研究人员建立了药物化学合作。他的团队已经实现了从简单材料开始直接合成 RocA 的多种结构类似物。我们共同的专业知识和资源确保了生物学研究的充足材料供应，不受有限自然资源的影响，并使我们能够进行初始结构活性关系（SAR）研究。这些已经鉴定出具有更有效的抗癌活性的化合物，但重要的靶点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”，将经过验证的 HTS 命中转化为有用的 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.