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

描述（由申请人提供）：目前，八分之一的妇女在一生中有患乳腺癌的风险。很大一部分乳腺癌患者发展为晚期或转移性乳腺癌，这些乳腺癌通常对常规抗癌疗法具有抗性并且无法治愈。目前的提议旨在开发抑制癌症进展、转移形成和对常规治疗的抗性的抗癌剂。乳腺肿瘤表达高水平的TGF-？以及促进转移和对治疗的抗性的活性NF-kB。TAK 1（TGF-β激活激酶1）介导TGF-β的原癌活性。癌症中的NFkB轴，激活导致侵袭性乳腺癌的分子途径，如ER阴性和HER 2阳性癌症，这些癌症难以用现有疗法治疗。我们开发了抑制TAK 1-NFkB轴致癌活性但不阻断TGF-β肿瘤抑制功能的合成化合物。这些药物是在一个集中的新合成化合物库的筛选中鉴定的，该化合物模拟了相对复杂的天然产物5 Z-7-oxozeaenol（一种有效的TAK 1抑制剂）的关键结构元素。两个化合物，HDAB 001和HDAB 006，表现出最有前途的性能，并将用于进一步优化作为候选药物。HDAB 001在小鼠临床前模型中降低了人乳腺癌异种移植物的生长，没有明显的副作用，如痛苦或体重减轻。 该提案旨在改善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目前的抗癌药物一起进行检查。具体目标1将优化所鉴定的先导化合物的功效和药理学性质。重点化学库的设计和合成将由埃默里大学化学系Huw Davies教授的小组进行，并将遵循严格的铅和候选药物指南。戴维斯小组将使用新的合成策略来化学合成新的化合物。目的2将在体外和体内临床前乳腺癌模型中检查聚焦化学文库的功能活性。RPCI的Bakin小组将对合成化合物进行生物学测试，询问主要药物特性（效力，选择性，目标）和作用机制。Davies和Bakin团队之间的合作对于项目的整体成功至关重要。如果成功，该研究将提供一种新型抗癌药物，其药理学特性优于现有药物，可单独使用或与常规疗法联合用于治疗晚期乳腺癌。最有前途的化合物将作为单一治疗或与常规药物联合用于I期临床试验的立即开发。

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.