Chemical probes that target Stat3 to treat cancer
靶向 Stat3 的化学探针可治疗癌症
基本信息
- 批准号:8311258
- 负责人:
- 金额:$ 27.74万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:3-DimensionalBindingBiological AssayBody Weight decreasedBone MarrowBreastCD44 geneCachexiaCancer PatientCellsChemicalsClinical TrialsCytoplasmDevelopmentDoseExhibitsFutureGene ExpressionGenerationsGrowthHumanImmunocompromised HostIn VitroInhibitory Concentration 50Interleukin-6LeadLibrariesLifeLigandsMalignant NeoplasmsMammary NeoplasmsMeasurableMediatingModelingModificationMusNuclear TranslocationParentsPathway interactionsPatientsPharmaceutical PreparationsPhasePhase I Clinical TrialsPhosphopeptidesPhosphorylationPopulationPreparationProteinsRecurrenceRelapseResidual TumorsResistanceSCID Beige MouseScreening procedureSignal TransductionSmall Business Technology Transfer ResearchStagingStructureSurface Plasmon ResonanceTestingTimeToxic effectToxicity TestsTransplantationTumor VolumeTumorigenicityXenograft ModelXenograft procedurebasecancer cellcancer stem cellcancer therapychemotherapyconventional therapydesignimprovedin vivoinhibitor/antagonistmalignant breast neoplasmnovelpharmacophorephase 1 studypre-clinicalpreventsarcopeniascaffoldself-renewalsmall hairpin RNAsmall moleculestemtherapy resistanttumortumor growthtumor xenografttumorigenicvirtual
项目摘要
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(由申请方提供):我们首次在人类乳腺癌患者中发现,标准化疗后的残留肿瘤富集了乳腺癌干细胞或肿瘤起始细胞(TIC)的CD 44 +/CD 24-/低群体,这些细胞表现出增强的乳腺球形成效率(MSFE),并显示小鼠异种移植物移植物生长增加(1,2,11)。此外,我们通过对CD 44 +/CD 24-/低乳腺球形成人群的基因表达分析和shRNA文库筛选确定,参与乳腺TIC自我更新的最重要的经典途径包括Stat 3信号传导(3)。使用虚拟配体筛选,我们鉴定了三种靶向Stat 3的Src同源(SH)2结构域并竞争性和选择性抑制Stat 3活化的小分子探针(5)。这些命中中最具活性的C188被证明可显著减少人到小鼠乳腺癌肿瘤移植物体积,并在与标准化疗联合使用时将移植小鼠的无肿瘤存活率提高4倍(3)。我们使用C188的支架作为查询结构和商业化合物库(Life Chemicals)进行2-D相似性筛选,然后进行3-D药效团分析,并鉴定了33种活性衍生物。目前StemMed拥有的一种衍生物(C188-9)在SPR测定中抑制Stat 3结合和阻断配体介导的Stat 3磷酸化方面比C188活性高1-log(6)。此外,C188-9在高达100 mg/kg/天的剂量下给药14天后,在小鼠中表现出极轻微的毒性,在体外未抑制正常小鼠骨髓集落形成,并在恶病质小鼠模型中预防体重减轻和肌肉减少症。将在本I期STTR中检查的具体假设是,C188-9或其衍生物之一将对Stat 3具有高度活性,在小鼠中耐受良好,并将在乳腺肿瘤移植模型中证明疗效。我们提出了2个密切关注的具体目标来实现这一假设:目的1:基于C188-9前导结构的修饰合成候选第三(第3)代C188探针,并鉴定具有增强效力和有利ADMET特征的探针。新探针的合成是简单的;具有更大效力和有利ADMET特征的探针将使用成熟的测定法进行鉴定。AIM 2.检查最有效和毒性最小的第3代Stat 3探针与标准化疗联合使用时靶向乳腺TIC和乳腺癌移植物生长的能力。两种C188-9衍生物是最有效的,毒性最小,并具有最好的ADMET特征,将检查其与标准化疗联合使用时靶向TIC和抑制肿瘤生长的能力,使用我们开发的29种乳腺肿瘤移植模型中信息量最大的子集。这些研究将为II期STTR应用奠定基础,我们将提出GMP合成和体内ADMET研究,研究在转移性乳腺癌I期临床试验准备中确定的最有前途的先导化合物。
公共卫生相关性:成功治愈对标准化疗有抵抗力的癌症将需要新的药物,包括那些针对称为癌症干细胞的癌细胞亚群的药物。癌症干细胞对标准化疗具有抗性,并且是肿瘤复发的原因。我们已经确定了乳腺癌干细胞中对其生存至关重要的途径,该途径涉及一种称为Stat 3的蛋白质,并在本申请中提出开发Stat 3的强效和选择性小分子抑制剂,用于开发转移性乳腺癌的新型有效药物治疗。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(3)
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David John Tweardy其他文献
David John Tweardy的其他文献
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{{ truncateString('David John Tweardy', 18)}}的其他基金
Project 2: Targeting STAT3 to Prevent Colorectal Cancer (CRC) in Hereditary Syndromes and Inflammatory Bowel Disease
项目2:靶向STAT3预防遗传综合征和炎症性肠病中的结直肠癌(CRC)
- 批准号:
10226089 - 财政年份:2019
- 资助金额:
$ 27.74万 - 项目类别:
Project 2: Targeting STAT3 with an Oral Small Molecule to Treat HCC
项目 2:用口服小分子靶向 STAT3 治疗 HCC
- 批准号:
10687041 - 财政年份:2019
- 资助金额:
$ 27.74万 - 项目类别:
Project 2: Targeting STAT3 with an Oral Small Molecule to Treat HCC
项目 2:用口服小分子靶向 STAT3 治疗 HCC
- 批准号:
10024078 - 财政年份:2019
- 资助金额:
$ 27.74万 - 项目类别:
Project 2: Targeting STAT3 with an Oral Small Molecule to Treat HCC
项目 2:用口服小分子靶向 STAT3 治疗 HCC
- 批准号:
10480100 - 财政年份:2019
- 资助金额:
$ 27.74万 - 项目类别:
Project 2: Targeting STAT3 to Prevent Colorectal Cancer (CRC) in Hereditary Syndromes and Inflammatory Bowel Disease
项目2:靶向STAT3预防遗传综合征和炎症性肠病中的结直肠癌(CRC)
- 批准号:
10415969 - 财政年份:2019
- 资助金额:
$ 27.74万 - 项目类别:
Project 2: Targeting STAT3 with an Oral Small Molecule to Treat HCC
项目 2:用口服小分子靶向 STAT3 治疗 HCC
- 批准号:
10246497 - 财政年份:2019
- 资助金额:
$ 27.74万 - 项目类别:
Targeting Stat1 and Stat3 to Reverse Radioresistance in Head and Neck Cancer
靶向 Stat1 和 Stat3 以逆转头颈癌的放射抗性
- 批准号:
8813192 - 财政年份:2014
- 资助金额:
$ 27.74万 - 项目类别:
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 - 财政年份:2012
- 资助金额:
$ 27.74万 - 项目类别:
Stat3 Probes that Target Breast Cancer Stem Cells
针对乳腺癌干细胞的 Stat3 探针
- 批准号:
8074424 - 财政年份:2010
- 资助金额:
$ 27.74万 - 项目类别:
Stat3 Probes that Target Breast Cancer Stem Cells
针对乳腺癌干细胞的 Stat3 探针
- 批准号:
7870842 - 财政年份:2010
- 资助金额:
$ 27.74万 - 项目类别:
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