Synthesis and biological screening of novel HIF-1α inhibitors for the treatment of breast cancer

摘要 治疗乳腺癌的新型HIF1α抑制剂 HIF1α(缺氧诱导因子)在许多类型的癌症中过表达，如乳腺癌。 目前还没有FDA批准的专门针对HIF-1α的药物。现有的低氧诱导因子-1α抑制剂 来自低选择性和高毒性。我们发现了一组新的小分子(CJ-3-60类似物) 基于广泛使用的缺氧诱导因子-1α抑制剂YC-1。初步数据显示，CJ-3-60的 对缺氧诱导因子-1α有较强的抑制作用，毒性低于YC-1。关于开发新型CJ-3-60类似物的建议研究 是高度创新的：首先，拟议的新类似物预计对乳房具有高度的选择性 癌细胞过表达HIF1α；第二，拟议的结构修饰将产生高度活性 具有可变微药代动力学特性的HIF-1α抑制剂，可实现最佳的肿瘤渗透 缺氧区，这是现有HIF-1α抑制剂的另一个主要限制。拟议的研究将提供 未来R01/SC1应用程序的概念验证，我们将在该应用程序中执行深入的机械研究， 全面的体内疗效和毒性研究。

Abstract Novel HIF1α Inhibitors for the Treatment of Breast Cancer HIF1α (hypoxia inducible factors) is overexpressed in many types of cancers such as breast cancer. Currently there is no FDA approved drug that specifically target HIF-1α. Existing HIF-1α inhibitors suffered from low selectivity and high toxicity. We have discovered novel sets of small molecules (CJ-3-60 analogs) based on a widely used HIF-1α inhibitor, YC-1. Preliminary data showed that CJ-3-60 is significantly more potent for HIF-1α inhibition and less toxic than YC-1. The proposed research to develop new CJ-3-60 analogs is highly innovative: First, the proposed new analogs are expected to have high selectivity against breast cancer cells overexpressing HIF1α; Second, the proposed structural modifications will generate highly active HIF-1α inhibitors with variable micropharmacokinetic properties that will allow for optimal penetration to tumor hypoxic regions which is another major limitation for existing HIF-1α inhibitors. The proposed study will provide proof-of-concept for a future R01/SC1 application in which we will perform in-depth mechanistic studies, comprehensive in vivo efficacy and toxicity studies.