A Novel STAT3 Inhibitor Targeting its DNA-Binding Site for Drug Development

 描述(申请人提供)：癌症是一个主要的公共卫生问题，也是导致死亡的主要原因，在美国每年夺走超过50万人的生命。虽然在开发靶向抗癌疗法方面取得了重大进展，但许多癌症，如肺癌，没有有效的治疗方法。不幸的是，许多理想的致癌靶点，包括这些癌症的转录因子，被认为是“不可用药的”，只是为了发现靶向治疗而回避。STAT3是Janus Kinase(JAK)/STAT信号通路中的一个转录因子，在包括肺癌和乳腺癌在内的大多数人类癌症中被结构性激活，并已被证明推动肿瘤的发生。因此，STAT3是发现抗癌药物的热门靶点。事实上，已经尝试将STAT3的SH2结构域作为药物发现的靶点。然而，这些抑制剂的临床疗效有限，其中一些在人体内的耐受性很差。另一方面，针对STAT3的DBS还没有出现在主流研究中，因为禁忌DNA结合位点(DBS)是“不可用药的”。利用一种改进的电子筛选方法，最近发现了一种针对STAT3的DBS的STAT3选择性小分子抑制剂(inS3-54)，它能有效地抑制癌细胞的增殖、迁移和侵袭。这些发现表明，STAT3的DBS可能是可用药的，挑战了DBS作为“不可用药”站点的普遍教条，并可能为难以治疗的人类癌症提供潜在的治疗方法。QRKAnswer，LLC是一家总部位于印第安纳州的小企业，其长期目标是研究针对STAT3的DBS的抑制剂，以进行潜在的药物开发。在这项第一阶段的STTR应用中，QRKAnswer和它在印第安纳大学医学院的研究伙伴计划研究inS3-54的活性类似物和新合成的物质组成，以确定潜在的抗癌药物开发的先导抑制剂。为此，将实现两个目标：(1)利用体外细胞分析评价S3-54类似物的活性和新的物质组成；(2)评价先导类似物的临床前药代动力学、毒性和疗效。在本研究结束时，QRKAnswer将有一种针对STAT3的DBS的先导抑制剂，具有第二阶段研究的临床前数据，在该研究中，QRKAnswer将进一步研究先导化合物，以提交IND并在2015年估计分别有234,190和221,200例新病例的实体肿瘤的I期临床试验中进行安全性测试。这一成功的结果将有助于QRKAnswer进入这个市场。

 DESCRIPTION (provided by applicant): Cancer is a major public health problem and a leading cause of mortality, claiming more than half million lives every year in the US. While major progresses have been made in developing targeted anticancer therapeutics, many cancers such as lung cancers have no effective treatments. Unfortunately, many ideal oncogenic targets including transcription factors for these cancers are considered "undruggable" and simply avoided for discovery of targeted therapeutics. STAT3, a transcription factor in the Janus kinase (JAK)/STAT signaling pathway, is constitutively activated in most human cancers including lung and breast cancers and has been shown to drive tumorigenesis. Thus, STAT3 is a sought-after target for discovery of anticancer drugs. Indeed, targeting the SH2 domain of STAT3 for drug discovery has been attempted. However, the clinical efficacy of these inhibitors is limited and some are poorly tolerated in humans. On the other hand, targeting the DBS of STAT3 has not been in the main stream of research due to the taboo that the DNA-binding site (DBS) is "undruggable". Using an improved in-silico screening approach, a STAT3-selective small molecule inhibitor (inS3-54) targeting the DBS of STAT3 was recently identified, which effectively inhibits cancer cell proliferation, migration, and invasion. These findings suggest tha the DBS of STAT3 may be druggable, challenging the prevailing dogma of DBS as an "undruggable" site and may promise a potential therapeutics for the difficult to treat human cancers. The long-term objective of QRKanswer, LLC, an Indiana-based small business, is to investigate inhibitors targeting the DBS of STAT3 for potential drug development. In this Phase I STTR application, QRKanswer and its research partners at Indiana University School of Medicine plan to investigate the active analogues of inS3-54 and newly synthesized new composition of matters to identify lead inhibitors for potential anticancer drug development. To this end, two aims will be accomplished to (1) evaluate the active inS3- 54 analogues and new composition of matters using in-vitro cell-based assays and (2) evaluate the lead analogues for preclinical pharmacokinetics, toxicity, and efficacy. At the conclusion of this study, QRKanswer will have a lead inhibitor targeting the DBS of STAT3 with preclinical data for Phase II study, in which QRKanswer will further investigate the lead compound for filing IND and potentially testing safety in phase I clinical trial of solid tumors such as breast and lung cancers with estimated 234,190 and 221,200 new cases in 2015, respectively. The successful outcome will help QRKanswer gain entry into this market.