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：
9288157
负责人：
Philip P Connell
金额：
$ 50.1万
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/9288157
关键词：
Animal Model Animals Antineoplastic Agents Biochemical Biological Assay 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 Interruption Lead Malignant Neoplasms Measures Mediating Metabolism Metastatic Neoplasm to the Lung Modification Mus Normal tissue morphology Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Property Proteins Rad51 recombinase Radiation Radiation therapy Resistance Specificity Structure Structure-Activity Relationship System Telomerase Testing Therapeutic Toxic effect Toxicity Tests Universities Up-Regulation Validation Work absorption base cancer cell cancer subtypes cancer type chemical synthesis chemotherapy drug candidate drug development drug discovery drug testing improved inhibitor/antagonist method development mouse model neoplastic cell novel oncology overexpression pre-clinical prevent protein aggregation protein complex public health relevance senescence small molecule telomere therapy resistant 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（通过应用提供）：人类恶性肿提取物的同源重组（HR）DNA修复水平升高，我们建议可以热探索这种恶性肿瘤的这种共同特征。我们通过开发专门抑制人力资源的药物并克服与癌细胞中HR上调相关的治疗耐药性来支持这一中心假设。我们的更新应用是基于这些药物发现工作的，并探索了针对中央HR蛋白的化合物的新颖应用，RAD51。该提案的主要假设和目标如下：首先，我们将进一步优化RAD51抑制性化合物，目的是克服肿瘤对化学疗法和放射疗法的抗性。我们将开发一种针对RAD51的专业活性的新型化合物，我们假设该活性会产生的毒性较少，而毒性比更广义的RAD51抑制剂。其次，我们假设RAD51抑制性化合物将使一种称为HR相关的机制，称为端粒的替代延长（ALT），这对于某些癌症亚型中的细胞增殖是必需的。由于正常的人类细胞仅利用端粒而不是ALT来维持其端粒，因此我们预测RAD51抑制作用将迫使Alt依赖性肿瘤细胞变为感应，而几乎没有正常的组织毒性。第三，我们假设Rad51刺激化合物可以特异性地促进过表达RAD51的肿瘤细胞死亡。这一概念是基于我们的观察结果，即高水平的RAD51过表达会导致癌细胞中不分泌染色质的毒性RAD51蛋白复合物的形成。我们还表明，Rad51刺激化合物在易感癌症类型中突出了这种潜在的毒性特征。所有这些假设都将使用相同的三个综合目的进行测试，该目标结合了广泛的药物开发方法。第一个目标将包括医学化学优化和ADMET测试。具体而言，我们的铅Rad51调节化合物的结构将通过旨在改善活性和药物特性的靶向化学修饰进行优化。在第二个目的中，我们将使用纯化的体外生化系统和基于细胞的刺激添加Rad51调节化合物的活性和特异性。第三个目标将验证动物模型中最高优先级化合物。 RAD51抑制性化合物将在两种小鼠模型中进行测试，以确认它们：1）敏感的人类肿瘤异种移植物可通过破坏化学治疗药物和/或辐射的复制治疗，以及2）防止Alt依赖性癌细胞在小鼠中形成肺转移。 Rad51刺激化合物将通过催化毒性RAD51蛋白质聚集在未分泌的染色质上测试易感肿瘤类型的能力。我们的最终目标是生成两个或三个候选药物，这些药物适用于临床试验中的扩展药物测试和随后的测试。