Targeting STAT3 as a novel approach to cancer therapy

项目总结/摘要 这项拨款提案的总体目标是发现基于设计小分子的新型抗癌药物。 在依赖于STAT3的肿瘤中抑制STAT3二聚化和异常功能的合成分子 STAT3用于生存。压倒性的临床前证据指出STAT3在肿瘤发生中的关键作用。 促进癌症的几个标志，包括不受控制的细胞增殖，凋亡逃避， 血管生成和转移。此外，临床上，在患者肿瘤中，发现STAT3持续高表达。 活化（酪氨酸磷酸化），这与化疗耐药性和预后不良有关。 在具有异常激活的STAT3的肿瘤细胞中，抑制STAT3功能， STAT3 β，敲低其表达或通过STAT3活化抑制剂抑制其活化， 逆转恶性转化和/或诱导细胞凋亡。STAT3酪氨酸磷酸化和 随后二聚化是STAT3激活所必需的。这项拨款所依据的假设 STAT3二聚化选择性抑制剂将抑制STAT3异常功能并抑制 STAT3介导的抗凋亡和/或促癌蛋白的上调，并将抑制肿瘤 生长并诱导凋亡。为了验证这一假设，提出了以下具体目标：1）使用 基于结构的虚拟HTS和分子建模，并进行实验HTS，以识别和设计 有效的和选择性的STAT3二聚化抑制剂。2)为了确定特定目标1至 有效并选择性地抑制STAT3二聚化、STAT3酪氨酸磷酸化、STAT3-DNA结合 和STAT3依赖性转录活性，3）为了确定高选择性STAT3是否 在具体目标2中鉴定的二聚化抑制剂能够有效地和选择性地抑制STAT3- 依赖于致癌信号传导并以STAT3依赖的方式抑制人类恶性转化 4）评价其抗肿瘤活性、药效学、药代动力学和毒性， 有效和选择性STAT3二聚化抑制剂的动物模型。拟议的研究将提供 化学探针，这将使我们能够加强我们对STAT3在人类中的重要性的理解。 肿瘤发生，并最终，研究将导致发现STAT3抑制剂与促凋亡和 抗肿瘤活性，并将拓宽可以成功治疗的人类肿瘤的范围。

Project Summary / Abstract The overall goal of this grant proposal is to discover novel anticancer drugs based on designing small synthetic molecules that inhibit STAT3 dimerization and aberrant function in tumors that depend on STAT3 for survival. Overwhelming pre-clinical evidence points to the pivotal involvement of STAT3 in promoting several hallmarks of cancer including uncontrolled cell proliferation, apoptosis evasion, angiogenesis, and metastasis. Furthermore, clinically, in patient tumors, STAT3 is found persistently hyper- activated (tyrosine phosphorylated) and this is associated with resistance to chemotherapy and poor prognosis. In tumor cells which harbor aberrantly activated STAT3, inhibiting STAT3 function with dominant negative STAT3 beta, knocking down its expression or inhibiting its activation by STAT3 activation inhibitors results in reversal of malignant transformation and/or induction of apoptosis. STAT3 tyrosine phosphorylation and subsequent dimerization are required for STAT3 activation. The hypothesis upon which this grant is based is that STAT3 dimerization selective inhibitors will suppress STAT3 aberrant function and inhibit STAT3-mediated up-regulation of anti-apoptotic and/or pro-oncogenic proteins, and will suppress tumor growth and induce apoptosis. To test this hypothesis the following specific aims are proposed: 1) To use structure-based Virtual HTS and molecular modeling and to perform experimental HTS to identify and design potent and selective STAT3 dimerization inhibitors. 2) To determine the ability of leads from Specific Aim 1 to potently and selectively inhibit STAT3 dimerization, STAT3 tyrosine phosphorylation, STAT3-DNA-binding and STAT3-dependent transcriptional activities in whole cells, 3) To determine if the highly selective STAT3 dimerization inhibitors identified in Specific Aim 2 are able to inhibit potently and selectively STAT3- dependent oncogenic signaling and suppress malignant transformation in a STAT3-dependent manner in human cancer cells, and 4) To evaluate the anti-tumor activity, pharmacodynamics, pharmacokinetics and toxicity in animal models of potent and selective STAT3 dimerization inhibitors. The studies proposed will provide chemical probes that will allow us to enhance our understanding of the importance of STAT3 in human oncogenesis, and ultimately, the studies will lead to the discovery of STAT3 inhibitors with pro-apoptotic and anti-tumor activities, and will broaden the spectrum of human tumors that can be successfully treated.