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

描述(申请人提供)：目前，每八名女性中就有一人有可能在一生中患上乳腺癌。相当大比例的乳腺癌患者发展为晚期或转移性乳腺癌，这些癌症往往对常规抗癌治疗耐药，而且无法治愈。目前的建议旨在开发抗癌药物，以抑制癌症的进展、转移的形成和对传统疗法的抵抗。乳腺肿瘤表达高水平的转化生长因子？？和活性的核因子-kB，促进转移和抵抗治疗。TAK1(转化生长因子-β-激活激酶1)在癌症中介导转化生长因子-β-NFkB轴的致癌活性，激活导致侵袭性乳腺癌的分子通路，如ER阴性和HER2阳性的乳腺癌，这些癌症很难用目前的治疗方法治疗。我们开发的合成化合物可以抑制TAK1-NFkB轴的致癌活性，但不会阻断转化生长因子-β的肿瘤抑制功能。这些药物是在模拟相对复杂的天然产物5Z-7-oxozeaenol的关键结构元素的新型合成化合物集中文库的筛选中确定的，5Z-7-oxozeaenol是TAK1的有效抑制剂。HDAB001和HDAB006这两个化合物表现出最有希望的性质，并将作为候选药物进行进一步的优化。HDAB001在小鼠临床前模型中减少了人乳腺癌移植瘤的生长，没有明显的副作用，如痛苦或体重减轻。该建议旨在改善已确定的先导化合物的功效和药理性质。我们将围绕先导化合物生成和测试重点化学库。最有希望的化合物将在临床前小鼠模型中单独或与当前的抗癌药物一起进行检验。具体目标1将优化已确定的先导化合物的功效和药理性质。重点化学库的设计和合成将由埃默里大学化学系休·戴维斯教授的团队进行，并将严格遵循铅和候选药物的指导方针。戴维斯团队将使用新的合成策略进行新化合物的化学合成。目的2将在体外和体内临床前乳腺癌模型中检测聚焦化学文库的功能活性。RPCI的巴金小组将对合成化合物进行生物测试，询问主要药物特性(效力、选择性、靶点)和作用机制。戴维斯和贝金小组之间的合作对该项目的全面成功至关重要。如果成功，这项研究将提供一类新的抗癌药物，具有比现有药物更好的药理特性，并可单独或与传统疗法结合用于治疗晚期乳腺癌。最有希望的化合物将作为单一疗法或与传统药物联合使用，立即用于I期临床试验。 公共卫生相关性：开发有效的治疗方法来阻止癌症的进展和转移是癌症治疗中的一项重要任务。目前的建议旨在开发以转化生长因子-β-NFkB轴上的TAK1为靶点的抗癌药物，以介导肿瘤的进展、转移的形成和对传统治疗的抵抗。如果成功，这项研究将提供新的抗癌化合物，比目前的治疗剂具有更好的药理特性。最有希望的化合物将作为单一疗法或与传统药物联合使用，立即用于I期临床试验。

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.