Development of inhibitors targeting the TGF-beta-NfkB axis in cancer

开发针对癌症中 TGF-β-NfkB 轴的抑制剂

• 批准号: 8243433
• 负责人: Andrei V. Bakin
• 金额: $ 17.5万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8243433
• 关键词: Adverse effects; Affect; Animals; Antineoplastic Agents; Area; Biological; Biological Assay; Biological Availability; Biological Factors; Biological Markers; Biological Testing; Body Weight decreased; Breast Cancer Treatment; Breast Carcinoma; Cancer Patient; Carcinoma; Cell Line; Cells; Chemicals; Chemistry; Clinical; Collaborations; Complex; Contracts; Development; Distress; Drug or chemical Tissue Distribution; ERBB2 gene; Elements; Evaluation; Exhibits; Feedback; Gene Expression Profiling; Goals; Growth; Guidelines; Head; Human; In Vitro; Lead; Legal patent; Libraries; Luciferases; MAP kinase kinase kinase 7; Malignant Neoplasms; Mammary Neoplasms; Mediating; Metabolic; Methodology; Modeling; Molecular; Mono-S; Mus; NF-kappa B; Neoplasm Metastasis; Oncogenic; Pathology; Pathway interactions; Pharmaceutical Preparations; Phase I Clinical Trials; Phosphotransferases; Pre-Clinical Model; Property; Proteins; Regimen; Reporter; Research Design; Resistance; Risk; Screening procedure; Signal Pathway; Specificity; Testing; Therapeutic; Therapeutic Agents; Toxic effect; Transforming Growth Factor beta; Tumor Suppressor Proteins; Universities; Woman; Work; Xenograft procedure; cancer therapy; chemical synthesis; conventional therapy; covalent bond; cytotoxicity; design; drug candidate; drug discovery; human MAP3K7 protein; improved; in vivo; inhibitor/antagonist; innovation; malignant breast neoplasm; mouse model; novel; pre-clinical; small molecule; small molecule libraries; success; therapeutic target; therapy resistant; tumor progression

DESCRIPTION (provided by applicant): Currently, one in eight women is at risk of contracting breast cancer in her lifetime. A significant proportion of breast cancer patients develop advanced or metastatic breast cancers that are frequently resistant to conventional anti-cancer therapy and incurable. The current proposal is aimed at the development of anti- cancer agents inhibiting cancer progression, formation of metastases and resistance to conventional therapy. Breast tumors express high levels of TGF-? and active NF-kB that promote metastases and resistance to therapy. TAK1 (TGF-beta-activated kinase 1) mediates the pro-oncogenic activities of the TGF-?-NFkB axis in cancer, activating molecular pathways contributing to aggressive breast cancers, such as ER-negative and HER2-positive cancers, that are difficult to treat with present therapies. We developed synthetic compounds that inhibit oncogenic activities of the TAK1-NFkB axis but do not block the tumor-suppressor function of TGF- ?. These agents were identified in the screen of a focused library of novel synthetic compounds mimicking the key structural elements of the relatively complex natural product 5Z-7-oxozeaenol, a potent inhibitor of TAK1. Two compounds, HDAB001 and HDAB006, exhibited the most promising properties and will be used for further optimization as drug candidates. HDAB001 decreased the growth of human breast carcinoma xenografts in a mouse pre-clinical model without noticeable side effects such as distress or weight loss. The proposal is aimed at improving the efficacy and pharmacological properties of the identified lead compounds. We will generate and test focused chemical libraries around the lead compounds. The most promising compounds will be examined alone or with current anti-cancer agents in preclinical mouse models. Specific Aim 1 will optimize the efficacy and pharmacological properties of the identified lead compounds. The focused chemical library design and synthesis will be performed by Prof. Huw Davies' group, Chemistry Department, Emory University, and will follow strict guidelines for lead and drug candidates. The Davies group will use novel synthetic strategies for chemical synthesis of novel compounds. Aim 2 will examine the functional activity of focused chemical libraries in in vitro and in vivo pre-clinical breast carcinoma models. The Bakin group at RPCI will perform biological testing of the synthetic compounds, interrogating major drug properties (potency, selectivity, targets) and mechanism of action. The collaboration between the Davies and Bakin groups is essential for the overall success of the project. If successful, the study will provide a novel class of anticancer agents with superior pharmacological properties over present agents and could be used alone or in combination with conventional therapy for treatment of advanced breast cancers. The most promising compounds will be available for immediate development of Phase I clinical trials as mono-therapy or in combination with conventional agents. PUBLIC HEALTH RELEVANCE: The development of effective therapeutics against cancer progression and metastasis is an important task in cancer treatment. The current proposal is aimed at the development of anticancer agents targeting TAK1 in the TGF-?-NFkB axis that mediates cancer progression, formation of metastases and resistance to conventional therapy. If successful, the study will provide novel anticancer compounds with improved pharmacological properties over present therapeutic agents. The most promising compounds will be available for immediate development of Phase I clinical trials as mono-therapy or in combination with conventional agents.

描述（由申请人提供）：目前，八分之一的女性一生中有患乳腺癌的风险。很大一部分乳腺癌患者患有晚期或转移性乳腺癌，这些癌症通常对传统抗癌治疗有抵抗力并且无法治愈。目前的提案旨在开发抑制癌症进展、转移形成和对常规治疗产生耐药性的抗癌药物。乳腺肿瘤表达高水平的 TGF-β以及促进转移和治疗抵抗的活性 NF-kB。 TAK1（TGF-β 激活激酶 1）介导癌症中 TGF-β-NFkB 轴的促癌活性，激活导致侵袭性乳腺癌（例如 ER 阴性和 HER2 阳性癌症）的分子途径，这些癌症用现有疗法难以治疗。我们开发了抑制 TAK1-NFkB 轴致癌活性但不阻断 TGF-β 肿瘤抑制功能的合成化合物。这些药物是在模拟相对复杂的天然产物 5Z-7-oxozeaenol（TAK1 的有效抑制剂）的关键结构元件的新型合成化合物重点库的筛选中鉴定出来的。 HDAB001和HDAB006这两种化合物表现出最有前途的特性，将作为候选药物用于进一步优化。 HDAB001 在小鼠临床前模型中减少了人乳腺癌异种移植物的生长，没有明显的副作用，例如痛苦或体重减轻。 该提案旨在提高已确定的先导化合物的功效和药理学特性。我们将围绕先导化合物生成并测试重点化学库。最有前途的化合物将在临床前小鼠模型中单独或与现有抗癌药物一起进行检查。具体目标 1 将优化已确定的先导化合物的功效和药理学特性。重点化学库的设计和合成将由埃默里大学化学系 Huw Davies 教授的团队进行，并将遵循针对先导药物和候选药物的严格指南。戴维斯小组将使用新颖的合成策略来化学合成新颖的化合物。目标 2 将检查重点化学文库在体外和体内临床前乳腺癌模型中的功能活性。 RPCI 的 Bakin 小组将对合成化合物进行生物测试，研究主要药物特性（效力、选择性、靶标）和作用机制。戴维斯和巴金小组之间的合作对于该项目的整体成功至关重要。如果成功，该研究将提供一类新型抗癌药物，其药理学特性优于现有药物，并且可以单独使用或与常规疗法联合使用来治疗晚期乳腺癌。最有前途的化合物将作为单一疗法或与常规药物联合用于立即开展 I 期临床试验。 公共卫生相关性：开发针对癌症进展和转移的有效疗法是癌症治疗的一项重要任务。目前的提案旨在开发针对 TGF-β-NFkB 轴中的 TAK1 的抗癌药物，该轴介导癌症进展、转移形成和对常规治疗的耐药性。如果成功，该研究将提供新型抗癌化合物，其药理学特性优于现有治疗剂。最有前途的化合物将作为单一疗法或与常规药物联合用于立即开展 I 期临床试验。