Chemical probes that target Stat3 to treat cancer

靶向 Stat3 的化学探针可治疗癌症

• 批准号: 8738035
• 负责人: David John Tweardy
• 金额: $ 13.9万
• 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/8738035
• 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 Profiling; 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; 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; screening; 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.

描述（由申请人提供）：我们在人类乳腺癌患者中首次表明，标准化疗后的残留肿瘤富含CD44+/CD24-/低乳腺癌茎或肿瘤发射细胞（TIC），这些细胞（TIC）表现出增强的哺乳动物形成效率（MSFE），并显示出脑植入式外植物外植物的增长（1），并表现出11次2次（1），1次2次，1次，1次，1次，1次，1次，1次，2次，2次，均为1次，1次，1次，1次，2次，2次，2次，1次，2次，2次，2次，1次，2次，1次，1次，2次，2次，1次，1次，2次，2个味道（1），1次，1个味道菌（1）。此外，我们从基因表达分析和shRNA文库筛选CD44+/CD24-/低乳球形成种群中确定，其中与乳腺抽动自我更新有关的顶级规范途径包括STAT3信号传导（3）。使用虚拟配体筛选，我们确定了针对SRC同源性（SH）2 STAT3域的三个小分子探针，并具有竞争性和选择性地抑制STAT3激活（5）。这些热门单曲中最活跃的C188被证明可以大大减少人类鼠类乳腺癌肿瘤的体积，并在结合标准化疗结合使用时增加4倍植入小鼠的肿瘤生存率（3）。我们使用C188的支架作为查询结构和商业化合物文库（Life Chemicals）进行了2-D相似性筛选，然后进行了3-D药效团分析，并确定了33个活性衍生物。一种衍生物（C188-9），现在由STEMMED拥有，在SPR分析中抑制STAT3结合并阻止配体介导的STAT3磷酸化时，在抑制STAT3结合时具有比C188更活跃（6）。此外，C188-9在小鼠中表现出最小的毒性，高达100 mg/kg/day 14天，在体外没有抑制正常的鼠骨髓菌落形成，并且在鼠模型中可以预防体重减轻和肌肉症。在这一阶段I STTR中将检查的具体假设是，C188-9或其衍生物之一将对STAT3具有很高的活性，在小鼠中将得到很好的耐受性，并且将在乳腺肿瘤模型中表现出疗效。我们提出了2个紧密集中的特定目的，以追求这一假设：目标1：基于C188-9的铅结构的修改，将候选者第三（第3）一代C188探针综合，并确定具有增加效力和有利ADMET特征的人。新探针的合成很简单。使用良好的测定法将确定具有更大效力和有利ADMET功能的探针。 AIM 2。要检查最有效和毒性的第三代STAT3探针，以靶向乳腺抽搐和抑制肿瘤的生长与标准化学疗法结合使用。两种C188-9衍生物是最有效，毒性最低，具有最佳的ADMET概况的衍生物，将使用我们开发的29个乳腺肿瘤模型中最有用的子集与标准化疗相结合时，可以检查靶向TIC和抑制肿瘤生长的能力。这些研究将为II期STTR应用奠定了阶段，我们将提出GMP合成和体内INTECHET研究，该研究是为准备在转移性乳腺癌中进行I期临床试验的最有希望的铅化合物。