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

一种针对 DNA 结合位点的新型 STAT3 抑制剂用于药物开发

• 批准号: 9047633
• 负责人: JingYuan Liu
• 金额: $ 27.98万
• 依托单位: QRKANSWER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9047633
• 关键词: Active Sites; Animal Model; Antineoplastic Agents; Apoptosis; Binding; Binding Sites; Biological Assay; Breast Cancer Model; Businesses; Cancer cell line; Categories; Cell Line; Cell Proliferation; Cells; Computer Simulation; DNA Binding; DNA-Binding Proteins; Data; Development; Disease; Drug Kinetics; EMSA; Evaluation; Human; In Vitro; Indiana; Janus kinase; Lead; Lung; Malignant Neoplasms; Malignant neoplasm of lung; Marketing; Maximum Tolerated Dose; Oncogenic; Outcome; Phase; Phase I Clinical Trials; Play; Proteins; Public Health; Research; Reverse Transcriptase Polymerase Chain Reaction; Role; STAT1 gene; Signal Pathway; Site; Small Business Technology Transfer Research; Solid Neoplasm; Stat3 protein; Stat5 protein; Stream; Taboo; Therapeutic; Time; Toxic effect; Universities; Western Blotting; Xenograft procedure; analog; anti-cancer therapeutic; base; cancer cell; cancer therapy; clinical efficacy; drug development; drug discovery; effective therapy; falls; improved; in vivo; inhibitor/antagonist; malignant breast neoplasm; medical schools; member; migration; mortality; new therapeutic target; novel; overexpression; phase 1 study; phase 2 study; pre-clinical; public health relevance; safety testing; screening; small molecule; small molecule inhibitor; src Homology Region 2 Domain; targeted treatment; transcription factor; triple-negative invasive breast carcinoma; tumorigenesis

 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.

 描述（由申请人提供）：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，在美国每年夺去50多万人的生命。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”，并简单地避免发现靶向治疗。STAT 3是Janus激酶（JAK）/STAT信号通路中的一种转录因子，在大多数人类癌症（包括肺癌和乳腺癌）中被组成性激活，并已显示出驱动肿瘤发生。因此，STAT 3是发现抗癌药物的一个受欢迎的靶标。事实上，已经尝试了靶向STAT 3的SH 2结构域用于药物发现。然而，这些抑制剂的临床疗效是有限的，有些人的耐受性差。另一方面，由于DNA结合位点（DBS）是“不可用药的”的禁忌，靶向STAT 3的DBS尚未成为研究的主流。使用改进的计算机筛选方法，最近鉴定了靶向STAT 3的DBS的STAT 3选择性小分子抑制剂（inS 3 -54），其有效地抑制癌细胞增殖、迁移和侵袭。这些发现表明，STAT 3的DBS可能是可药物化的，挑战了DBS作为“不可药物化”位点的流行教条，并可能为难以治疗的人类癌症提供潜在的治疗方法。QRKanswer，LLC是一家位于印第安纳州的小企业，其长期目标是研究针对STAT 3 DBS的抑制剂，以用于潜在的药物开发。在这项I期STTR申请中，QRKanswer及其在印第安纳州大学医学院的研究合作伙伴计划研究inS 3 -54的活性类似物和新合成的新物质组合物，以确定潜在抗癌药物开发的先导抑制剂。为此，将实现两个目标：（1）使用基于细胞的体外试验评价活性inS 3 - 54类似物和物质的新组合物;（2）评价先导类似物的临床前药代动力学、毒性和疗效。在这项研究结束时，QRKanswer将有一种靶向STAT 3 DBS的先导抑制剂，并有II期研究的临床前数据，其中QRKanswer将进一步研究先导化合物，以提交IND，并可能在实体瘤（如乳腺癌和肺癌）的I期临床试验中测试安全性，预计2015年将分别有234，190和221，200例新病例。成功的结果将有助于QRKanswer进入这个市场。