Chemical probes that target Stat3 to treat cancer

靶向 Stat3 的化学探针可治疗癌症

• 批准号: 8311258
• 负责人: David John Tweardy
• 金额: $ 27.74万
• 依托单位: STEMMED, LTD
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-26 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8311258
• 关键词: 3-Dimensional; Binding; Biological Assay; Body Weight decreased; Bone Marrow; Breast; CD44 gene; Cachexia; Cancer Patient; Cells; Chemicals; Clinical Trials; Cytoplasm; Development; Dose; Exhibits; Future; Gene Expression; Generations; Growth; Human; Immunocompromised Host; In Vitro; Inhibitory Concentration 50; Interleukin-6; Lead; Libraries; Life; Ligands; Malignant Neoplasms; Mammary Neoplasms; Measurable; Mediating; Modeling; Modification; Mus; Nuclear Translocation; Parents; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Phosphopeptides; Phosphorylation; Population; Preparation; Proteins; Recurrence; Relapse; Residual Tumors; Resistance; SCID Beige Mouse; Screening procedure; Signal Transduction; Small Business Technology Transfer Research; Staging; Structure; Surface Plasmon Resonance; Testing; Time; Toxic effect; Toxicity Tests; Transplantation; Tumor Volume; Tumorigenicity; Xenograft Model; Xenograft procedure; base; cancer cell; cancer stem cell; cancer therapy; chemotherapy; conventional therapy; design; improved; in vivo; inhibitor/antagonist; malignant breast neoplasm; novel; pharmacophore; phase 1 study; pre-clinical; prevent; sarcopenia; scaffold; self-renewal; small hairpin RNA; small molecule; stem; therapy resistant; tumor; tumor growth; tumor xenograft; tumorigenic; virtual

DESCRIPTION (provided by applicant): We have shown for the first time in human breast cancer patients that residual tumors after standard chemotherapy are enriched for a CD44+/CD24-/low population of breast cancer stem or tumor-initiating cells (TIC) that exhibit enhanced mammosphere-forming efficiency (MSFE) and display an increase in xenograft transplant outgrowths in mice (1, 2, 11). In addition, we have determined from gene expression analysis and shRNA library screening of the CD44+/CD24-/low-mammosphere-forming population that the top canonical pathways involved in breast TIC self-renewal include Stat3 signaling (3). Using virtual ligand screening, we identified three small-molecule probes that target the Src homology (SH) 2 domain of Stat3 and that competitively and selectively inhibited Stat3 activation (5). The most active of these hits, C188, was shown to dramatically reduce human-into-mouse breast cancer tumorgraft volumes and to increase tumor-free survival of engrafted mice 4-fold when used in combination with standard chemotherapy (3). We performed 2-D similarity screening using the scaffold of C188 as the query structure and a commercial compound library (Life Chemicals) followed by 3-D pharmacophore analysis and identified 33 active derivatives. One derivative (C188-9), now owned by StemMed, is 1-log more active than C188 at inhibiting Stat3 binding in SPR assays and in blocking ligand-mediated Stat3 phosphorylation (6). In addition, C188-9 exhibited minimal toxicity in mice up to a dose of 100 mg/kg/day for 14 days, did not inhibit normal murine bone marrow colony formation in vitro, and, prevented weight loss and sarcopenia in a murine model of cachexia. The specific hypothesis that will be examined in this Phase I STTR is that C188-9 or one of its derivatives will be highly active against Stat3, will be well tolerated in mice, and will demonstrate efficacy in breast tumorgraft models. We have proposed 2 tightly focused specific aims to pursue this hypothesis: AIM 1: To synthesize candidate third (3rd) generation C188 probes based on modifications of the C188-9 lead structure and to identify those with increased potency and favorable ADMET features. Synthesis of new probes is straightforward; probes with greater potency and favorable ADMET features will be identified using well-established assays. AIM 2. To examine the most potent and least toxic 3rd generation Stat3 probes for the ability to target breast TICs and inhibi tumorgraft growth when used in combination with standard chemotherapy. Two C188-9 derivatives that are the most potent, least toxic, and have the best ADMET profile will be examined for the ability to target TIC and inhibit tumor growth when combined with standard chemotherapy using the most informative subset of the 29 breast tumorgraft models we have developed. These studies will set the stage for a Phase II STTR application in which we will propose GMP synthesis and in vivo ADMET studies of the most promising lead compound identified in preparation for a Phase I clinical trial in metastatic breast cancer. PUBLIC HEALTH RELEVANCE: Successfully curing cancers that are resistant to standard chemotherapy will require new drugs including those directed at a subset of cancer cells referred to as cancer stem cells. Cancer stem cells are resistant to standard chemotherapy and are responsible for tumor recurrence. We have identified a pathway in breast cancer stem cells essential for their survival that involves a protein called Stat3 and propose in this application t develop potent and selective small-molecule inhibitors of Stat3 for development into a novel and effective drug treatment for metastatic breast cancer.

描述(申请人提供)：我们首次在人类乳腺癌患者身上显示，标准化疗后的残余肿瘤被浓缩为CD44+/CD24-/低数量的乳腺癌干细胞或肿瘤启动细胞(TIC)，显示出增强的乳房形成效率(MSFE)，并显示小鼠异种移植生长增加(1，2，11)。此外，我们从CD44+/CD24-/低乳房形成人群的基因表达分析和shRNA文库筛选中确定，参与乳房TIC自我更新的最典型的通路包括STAT3信号转导(3)。通过虚拟配体筛选，我们确定了三个针对STAT3的Src同源(SH)2结构域的小分子探针，它们竞争性地和选择性地抑制了STAT3的激活(5)。其中最活跃的C188被证明可以显著减少人-鼠乳腺癌移植瘤的体积，并在与标准化疗联合使用时将移植鼠的无瘤存活率提高4倍(3)。我们以C188为骨架，以商业化合物文库(生命化学)为查询结构，进行二维相似性筛选，然后进行三维药效团分析，鉴定出33个活性衍生物。一种衍生物(C188-9)，现在归Stemed所有，在SPR分析中抑制STAT3结合和阻断配体介导的STAT3磷酸化方面比C188活性高1log(6)。此外，C188-9对小鼠的毒性最小，剂量为100 mg/kg/d，连续14天，不抑制正常小鼠骨髓细胞在体外的集落形成，并防止体重减轻和恶病质小鼠模型的骨肉减少。将在这一第一阶段STTR中检验的具体假设是，C188-9或其衍生物之一将对STAT3具有高度活性，在小鼠中具有良好的耐受性，并将在乳腺肿瘤移植模型中展示有效性。为了实现这一假说，我们提出了两个高度集中的特定目标：目标1：基于C188-9前导结构的修改合成候选的第三代(第3代)C188探针，并鉴定那些具有更高效力和良好的admet特征的探针。新探针的合成很简单；具有更大效力和良好的ADMET特征的探针将使用成熟的分析方法进行鉴定。目的2.检测最有效和毒性最低的第三代STAT3探针与标准化疗联合使用时靶向乳房痉挛和抑制肿瘤生长的能力。我们将使用我们开发的29个乳腺肿瘤移植模型中信息最丰富的子集，检查两种最有效、毒性最低、具有最佳ADMET配置文件的C188-9衍生物在与标准化疗相结合时靶向TIC和抑制肿瘤生长的能力。这些研究将为第二阶段STTR的应用奠定基础，我们将提出GMP合成和体内ADMET研究，为转移性乳腺癌的第一阶段临床试验准备中确定的最有希望的先导化合物。 与公共卫生相关：成功治愈对标准化疗耐药的癌症将需要新药，包括那些针对癌症干细胞的癌症细胞子集的药物。癌症干细胞对标准化疗有抵抗力，是肿瘤复发的原因。我们已经在乳腺癌干细胞中发现了一条对其生存至关重要的途径，该途径涉及一种名为STAT3的蛋白质，并建议在这一应用中开发有效和选择性的STAT3小分子抑制剂，以开发成一种治疗转移性乳腺癌的新的有效药物。