Novel DNA-metalating Hybrid Anticancer Agents

新型 DNA 金属化混合抗癌剂

基本信息

批准号：
7845080
负责人：
Ulrich Bierbach
金额：
$ 23.14万
依托单位：
WAKE FOREST UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-07-01 至 2013-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7845080
关键词：
Acridines Adenine Adverse effects Affect Antineoplastic Agents Basic Science Binding Biological Biological Assay Cancer cell line Cell Death Cell-Free System Cells Chemical Structure Chemicals Chemistry Chemotherapy-Oncologic Procedure Chromatin Structure Cisplatin Clinic Clinical DNA DNA Adducts DNA Binding DNA Damage DNA lesion Development Drug Delivery Systems Drug Kinetics Drug Metabolic Detoxication Frequencies Gel Glutathione Goals Hybrids In Vitro Intercalating Agents Interdisciplinary Study Intervention Lead Lesion Libraries Ligands Major Groove Malignant Neoplasms Mammalian Cell Metals Minor Groove Modification Molecular Nitrogen Non-Small-Cell Lung Carcinoma Nuclear Nucleotide Excision Repair Pathway interactions Pharmaceutical Preparations Pharmacodynamics Platinum Platinum Compounds Purines Reaction Regimen Research Resistance Salvage Therapy Screening procedure Site Solid Neoplasm Staging Structure Structure-Activity Relationship Testing Unresectable Xenograft Model adduct analog base cancer cell cancer therapy cell killing chemical property chemotherapy combinatorial crosslink cytotoxic cytotoxicity design drug development improved in vivo novel nucleobase patient population pharmacophore pre-clinical preclinical study programs prototype public health relevance purine repaired research study response structural biology therapy design tumor

项目摘要

DESCRIPTION (provided by applicant): This application outlines a multidisciplinary research program at the cross-section of anticancer drug development, molecular and structural biology, and biocoordination chemistry. The proposed research was sparked by the recent discovery of the unusual DNA damage profile of a cytotoxic platinum-acridine hybrid agent ("PT-ACRAMTU"). Unlike the clinical cisplatin-based agents, this drug does not cross-link DNA bases but induces structurally unique coordinative-intercalative monoadducts in both the DNA major and minor grooves. In particular, the formation of adducts with adenine-N3 in the minor groove is a damage mechanism previously unknown in platinum antitumor chemistry. Novel types of DNA lesions, such as PT-ACRAMTU's monoadducts, have the potential to overcome tumor resistance by providing alternate pathways to cell death and therefore should be pursued rigorously at the preclinical development stage. PT-ACRAMTU-type conjugates have demonstrated enhanced cytotoxic activity compared with cisplatin in various solid tumors, especially non-small cell lung cancers (NSCLC), which are difficult to treat with current regimens. Spanning the range from basic science to biomedical application, the proposed experiments aim to unravel the agent's unusual DNA-binding mechanism and elucidate the DNA structural impact caused by its adducts. The results expected from these studies will be used to develop the prototypical agent, which has already demonstrated potent activity in xenograft models, into a clinically useful therapy that acts through a mechanism unlike that of clinical platinum drugs. Specifically, the research will (1) use modular synthesis to produce PT-ACRAMTU derivatives with enhanced target selectivity and minimal side effects, (2) study their DNA-damage profiles using newly developed (bio)chemical assays, (3) test the hypothesis that PT-ACRAMTU-type adducts are able to evade nucleotide excision repair (NER) because they do not bend or destabilize DNA, and (4) establish relationships between chemical properties, the specific type of lesion formed within nuclear DNA, its persistence in NER-proficient cells, and its cytotoxic and antitumor potential. Thus, the study holds considerable promise of providing novel chemotypes that show activity in tumors inherently insensitive to platinum and chemotherapeutic intervention in general and salvage therapies for cancers that have acquired resistance to cisplatin and other DNA-targeted drugs. PUBLIC HEALTH RELEVANCE: The research described in this proposal is centered on the development of a new platinum-based cancer treatment for chemoresistant using a unique chemical approach. The study has the potential to identify a new class of anticancer drugs for the management of intractable tumors, especially non-small cell lung carcinomas (NSCLC), based on a unique mechanism of action at the cancer cell's DNA previously unknown for platinum containing chemotherapies currently used in the clinic.

描述（由申请人提供）：本申请概述了抗癌药物开发、分子和结构生物学以及生物配位化学等交叉领域的多学科研究计划。这项拟议的研究是由最近发现的一种细胞毒性铂-吖啶混合剂（“PT-ACRAMTU”）的不寻常 DNA 损伤特征引发的。与临床上基于顺铂的药物不同，该药物不会交联 DNA 碱基，而是在 DNA 大沟和小沟中诱导结构独特的配位嵌入单加合物。特别是，小沟中与腺嘌呤-N3 形成加合物是铂抗肿瘤化学中以前未知的损伤机制。新型 DNA 损伤，例如 PT-ACRAMTU 的单加合物，有可能通过提供细胞死亡的替代途径来克服肿瘤耐药性，因此应在临床前开发阶段进行严格研究。与顺铂相比，PT-ACRAMTU 型缀合物在各种实体瘤中表现出增强的细胞毒活性，尤其是目前难以治疗的非小细胞肺癌 (NSCLC)。拟议的实验涵盖从基础科学到生物医学应用的范围，旨在解开该药物不寻常的 DNA 结合机制，并阐明其加合物引起的 DNA 结构影响。这些研究的预期结果将用于开发原型药物，该药物已在异种移植模型中表现出有效的活性，成为一种临床上有用的疗法，其作用机制与临床铂类药物不同。具体来说，该研究将 (1) 使用模块化合成来生产具有增强的靶标选择性和最小副作用的 PT-ACRAMTU 衍生物，(2) 使用新开发的（生物）化学测定法研究其 DNA 损伤概况，(3) 检验假设PT-ACRAMTU 型加合物能够逃避核苷酸切除修复 (NER)，因为它们不会弯曲或破坏 DNA 的稳定性，并且 (4) 建立化学性质、核 DNA 内形成的特定损伤类型、其NER 熟练细胞中的持久性及其细胞毒性和抗肿瘤潜力。因此，这项研究有望提供新的化学型，这些化学型在肿瘤中显示出对铂不敏感的活性，并且一般而言化学治疗干预以及对顺铂和其他 DNA 靶向药物产生耐药性的癌症的挽救疗法。公共健康相关性：本提案中描述的研究重点是使用独特的化学方法开发一种新的铂基癌症治疗方法，用于治疗耐药性。该研究有可能确定一类新的抗癌药物，用于治疗顽固性肿瘤，特别是非小细胞肺癌 (NSCLC)，其基础是对癌细胞 DNA 的独特作用机制，而目前的含铂化疗尚不清楚用于临床。