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协调化学的横截面上的多学科研究计划。拟议的研究是通过最近发现的细胞毒性铂 - acridine杂种剂（“ PT-Acramtu”）的异常DNA损伤曲线引发的。与临床顺铂的剂不同，该药物不会交联的DNA碱基，而是在DNA主要和小凹槽中诱导结构独特的协调间隔单载剂。特别是，在小凹槽中与腺嘌呤-N3的加合物形成是铂抗肿瘤化学中以前未知的损伤机制。新型的DNA病变（例如PT-Acramtu的单核）具有通过提供替代细胞死亡途径来克服肿瘤耐药性的潜力，因此应在临床前发育阶段进行严格追求。在各种实体瘤中，尤其是非小细胞肺癌（NSCLC），与顺铂相比，PT-Acramtu-type结合物与顺铂相比已显示出增强的细胞毒性活性，这些癌症很难用当前方案治疗。跨越从基础科学到生物医学应用的范围，拟议的实验旨在揭开药物的异常DNA结合机制，并阐明其加合物引起的DNA结构影响。这些研究预期的结果将用于开发原型剂，该原型剂已经在异种移植模型中证明了有效的活性，以一种临床上有用的疗法，该疗法与临床铂药不同的机制作用。 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）建立化学性质之间的关系，核DNA中形成的特定病变类型，其在NER良好细胞中的持久性以及其细胞毒性和抗肿瘤潜力。因此，该研究具有相当大的希望，可以提供新型的化学型，这些化学型在肿瘤中对铂和化学治疗干预的固有不敏感的活性，并为对顺铂和其他诱导DNA靶向药物的抗性的癌症提供了一般和挽救疗法。公共卫生相关性：该提案中描述的研究以使用独特的化学方法的化学耐药性为基于铂金的癌症治疗的开发为中心。这项研究有可能根据癌细胞的独特作用机制，以识别一种新的抗癌药物，尤其是非小细胞肺癌（NSCLC），以治疗非小细胞肺癌（NSCLC）。