Novel STAT3 inhibitor for overcoming chemoresistant ovarian cancer .

摘要/概要 上皮性卵巢癌（OC）是女性死亡的第五大原因，也是最致命的妇科疾病。 美国的恶性肿瘤。OC大多在晚期被诊断。患者接受减积 手术和化疗或新辅助化疗和间隔减瘤手术。常规药物 是卡铂和紫杉醇尽管最近引入了FDA批准的PARP和VEGF抑制剂， OC，绝大多数患者将经历需要额外治疗的疾病复发， 复发性OC基本上无法治愈。需要新的治疗方法来改善患者的预后。转录 已经证明，主转录调节因子STAT 3在OC中是高度活跃的， 通过增加SH 2-二聚化结构域（pSTAT 3-Y 705）中的磷酸化和致癌因子的诱导。 转移性和化疗耐药OC中的活性STAT 3与患者生存率差相关，抑制STAT 3 用shRNA或小分子抑制OC进展，支持靶向STAT 3作为治疗OC进展的目标。 可行的治疗策略。此外，我们证明了在OC细胞中STAT 3活性的显著上调， 与增加的铂电阻密切相关。我们假设靶向STAT 3将阻断 多种致癌途径，并使OC细胞对化疗敏感。虽然转录因子（TF）如 STAT 3是有吸引力的治疗靶点，TF由于缺乏明确的靶点而难以用小分子靶向。 小分子结合口袋、对蛋白质-蛋白质相互作用重要的大表面积和大的 本质上无序的畴。在Altay Therapeutics，我们开发了一个平台，可以识别 小分子结合口袋内的固有无序结构域在以前不可药的TF，允许 一种特异性靶向STAT 3和开发有效的STAT 3抑制剂（STAT 3 i）的新方法。使用 在我们的平台上，我们通过靶向无序的DNA结合来识别减少STAT 3 DNA结合的抑制剂 域重要的是，这些STAT 3 i具有最小的STAT 1抑制活性、低细胞毒性，并且当用于 与CDDP组合，在OC细胞系中协同并增加铂敏感性。我们提出了三 基于定量指标的目标，将明确定义抑制STAT 3的最佳候选物， 现有的STAT 3和阻断OC进展。在目标1中，我们将确定STAT 3靶基因抑制， 用Altay的新型STAT 3 is测量对分泌的炎症因子的影响。在目标2中，我们将在体外进行 使用STAT 31与铂的组合对人和转基因小鼠OC细胞进行的表型研究 化疗在目的3中，我们将使用原位和原位OC细胞测定STAT 3 i的抗肿瘤活性。 腹膜内体内模型单独和与铂化疗组合。拟议的研究将 确立靶向STAT 3治疗化疗耐药OC的潜力，并指导新的治疗策略 在这种情况下。然后，我们将寻求SBIR第2阶段赠款，将包括药物化学的努力， 另外的动物研究，并最终商业化的第一类STAT 3抑制剂的OC。

Abstract/Summary Epithelial ovarian cancer (OC) is the fifth leading cause of death in women and the most lethal gynecological malignancy in the United States. OC is mostly diagnosed at an advanced stage. Patients undergo debulking surgery and chemotherapy or neoadjuvant chemotherapy and interval debulking surgery. Conventional drugs are carboplatin and paclitaxel. Despite the recent introduction of FDA-approved PARP- and VEGF-inhibitors for OC, the vast majority of patients will experience disease recurrence that requires additional treatment and recurrent OC is essentially incurable. New therapeutics to improve patient outcomes are needed. Transcriptional profiles have demonstrated that the master transcriptional regulator STAT3 to be highly active in OC, determined by increased phosphorylation in SH2-dimerization domain (pSTAT3-Y705) and induction of oncogenic factors. Active STAT3 in metastatic and chemoresistant OC correlates with poor patient survival, and inhibiting STAT3 with shRNA, or small molecules inhibited OC progression, supporting the objective of targeting STAT3 as a viable therapeutic strategy. Additionally, we demonstrate significant upregulation of STAT3 activity in OC cells is strongly associated with increased platinum resistance. We hypothesize that targeting STAT3 will block multiple oncogenic pathways and sensitize OC cells to chemotherapy. Although transcriptions factors (TF) like STAT3 are attractive therapeutic targets, TFs are challenging to target with small molecules due to lack of clear small molecule binding pockets, large surface areas important for protein-protein interactions and large intrinsically disordered domains. At Altay Therapeutics, we developed a platform that enables identification of small molecule binding pockets within intrinsically disordered domains in previously undruggable TFs, allowing a novel approach for specific targeting of STAT3 and development of potent STAT3 inhibitors (STAT3i). Using our platform, we identified inhibitors that reduced STAT3 DNA binding by targeting the disordered DNA binding domain. Importantly, these STAT3i have minimal STAT1 inhibitory activity, low cytotoxicity and when used in combination with CDDP, synergized and increased platinum sensitivity across OC cell lines. We propose three aims based on quantitative metrics that will clearly define the top candidate(s) which inhibit STAT3 compared to existing STAT3is and block OC progression. In Aim 1, we will determine STAT3 target gene inhibition and measure effects on secreted inflammatory factors with Altay’s novel STAT3is. In Aim 2, we will carry out in vitro phenotypic studies with human and transgenic mouse OC cells using STAT3is in combination with platinum chemotherapy. In Aim 3, we will determine antitumor activity of STAT3i using OC cells in orthotopic and intraperitoneal in vivo models alone and in combination with platinum chemotherapy. The proposed studies will establish the potential for targeting STAT3 in treating chemoresistant OC and guide new therapeutic strategies in this setting. We will then pursue an SBIR phase 2 grant that will include medicinal chemistry efforts and additional animal studies and ultimately commercialization of a first-in-class STAT3 inhibitor for OC.