RAD51 Inhibitors for Chemotherapy and Radiation Therapy

用于化疗和放疗的 RAD51 抑制剂

基本信息

批准号：
8961931
负责人：
Philip P Connell
金额：
$ 51.55万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-03-16 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8961931
关键词：
Animal Model Animals Antineoplastic Agents Biochemical Biological Assay Boxing Cell Proliferation Cells Cessation of life Chemicals Chicago Chromatin Clinical Trials Computer Simulation DNA Damage DNA Repair DNA biosynthesis Excretory function Exhibits Funding Goals Growth Human Illinois In Vitro Lead Lung Malignant Neoplasms Measures Mediating Metabolism Methods Modification Mus Neoplasm Metastasis Normal tissue morphology Pharmaceutical Chemistry Pharmaceutical Preparations Property Rad51 recombinase Radiation Radiation therapy Resistance Specificity Structure Structure-Activity Relationship System Telomerase Testing Toxic effect Toxicity Tests Universities Up-Regulation Validation Work absorption base cancer cell cancer type chemical synthesis chemotherapy drug candidate drug development drug discovery improved inhibitor/antagonist mouse model neoplastic cell novel oncology overexpression prevent protein aggregation protein complex public health relevance research clinical testing senescence small molecule telomere tumor tumor xenograft

项目摘要

DESCRIPTION (provided by applicant): Human malignancies exhibit elevated levels of homologous recombinational (HR) DNA repair proficiency, and we propose that this common feature of malignancy can be exploited therapeutically. We have supported this central hypothesis by developing drug candidates that specifically inhibit HR and overcome the treatment resistance associated with HR up-regulation in cancer cells. Our renewal application builds on these drug discovery efforts and explores novel applications for compounds that target the central HR protein, RAD51. The major hypotheses and goals of this proposal are as follow: First, we will further optimize RAD51-inhibitory compounds with the goal of overcoming tumor resistance to chemotherapy and radiotherapy. We will develop a novel class of compounds that target a specialized activity of RAD51, which we hypothesize will generate less toxicity than more generalized RAD51 inhibitors. Second, we hypothesize that RAD51-inhibitory compounds will inactivate an HR-related mechanism called alternative lengthening of telomere (ALT), which is required for cell proliferation in some cancer subtypes. Since normal human cells exclusively utilize telomerase instead of ALT to maintain their telomeres, we predict that RAD51 inhibition will force ALT-dependent tumor cells into senescence while exerting little or no normal tissue toxicity. Third, we hypothesize that RAD51-stimulatory compounds can specifically promote death in tumor cells that overexpress RAD51. This concept builds on our observations that high levels of RAD51 overexpression cause the formation of toxic RAD51 protein complexes on undamaged chromatin in cancer cells. We have also shown that RAD51-stimulatory compounds accentuate this potentially toxic feature in susceptible cancer types. All of these hypotheses wil be tested using the same three integrated aims, which incorporate a wide range of drug development methods. The first aim will consist of medicinal chemistry optimization and ADMET testing. Specifically, the structures of our lead RAD51-modulating compounds will be optimized via targeted chemical modifications aimed at improving both activity and pharmacologic properties. In the second aim, we will characterize the activity and specificity of RAD51-modulating compounds, using both purified in vitro biochemical systems and cell-based assays. The third aim will validate the highest priority compounds in animal models. RAD51-inhibitory compounds will be tested in two mouse models to confirm that they: 1) sensitize human tumor xenografts to treatment with replication-disrupting chemotherapeutic drugs and/or radiation, and 2) prevent the ALT-dependent cancer cells from forming lung metastases in mice. RAD51- stimulatory compounds will be tested for the ability to shrink susceptible tumor types, by catalyzing toxic RAD51 protein aggregation on undamaged chromatin. Our ultimate goal is to generate two or three drug candidates that are suitable for extended pharmacologic testing and subsequent testing in clinical trials.

描述（由申请人提供）：人类恶性肿瘤表现出同源重组（HR）DNA修复能力水平升高，我们建议可以在治疗上利用恶性肿瘤的这一共同特征。我们支持了由特异性抑制HR的候选药物开发的这一中心假设。并克服与癌细胞 HR 上调相关的治疗耐药性。我们的更新应用建立在这些药物发现工作的基础上，并探索针对中心 HR 蛋白 RAD51 的化合物的新应用。该提案的目标如下：首先，我们将进一步优化 RAD51 抑制化合物，以克服肿瘤对化疗和放疗的耐药性。我们将开发一类针对 RAD51 特殊活性的新型化合物。其次，我们发现 RAD51 抑制化合物会灭活一种称为端粒选择性延长 (ALT) 的 HR 相关机制，该机制是某些细胞增殖所必需的。由于正常人类细胞利用端粒酶而不是 ALT 来维持其端粒，我们预测 RAD51 抑制将迫使 ALT 依赖性肿瘤细胞进入衰老状态，同时对正常组织产生很少或不产生毒性。特异性促进过度表达 RAD51 的肿瘤细胞死亡这一概念建立在我们的观察基础上，即高水平的 RAD51 过度表达会导致有毒 RAD51 蛋白复合物的形成。我们还表明，RAD51 刺激化合物会加剧易感癌症类型的这种潜在毒性特征，所有这些假设都将使用相同的三个综合目标进行测试，其中首先包含广泛的药物开发方法。具体来说，我们的主要 RAD51 调节化合物的结构将通过化学修饰进行优化，旨在提高活性和药理学特性。第三个目标是使用纯化的体外生化系统和基于细胞的测定来验证 RAD51 调节化合物的活性和特异性，将在两种小鼠模型中测试最优先的化合物。：1) 使人类肿瘤异种移植物敏感，以使用破坏复制的化疗药物和/或放射治疗，以及 2) 防止 ALT 依赖性癌细胞在体内形成肺转移我们将通过催化未受损染色质上的有毒 RAD51 蛋白聚集来测试 RAD51 刺激化合物缩小易感肿瘤类型的能力，我们的最终目标是产生两种或三种适合进行扩展药理学测试和后续测试的候选药物。临床试验。