A Unique Class of Reductively Activated Oncology Drugs

一类独特的还原激活肿瘤药物

基本信息

批准号：
10116967
负责人：
DALE L BOGER
金额：
$ 71.9万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-03-14 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10116967
关键词：
Address Aminophenols Antineoplastic Agents Behavior Blood - brain barrier anatomy Bone Marrow Cancer Patient Chemicals Clinic Clinical Clinical Trials Delayed-Action Preparations Development Disease Dose Drug Design Drug resistance Duocarmycin Electrons Environment Enzymes Evaluation Exhibits Fostering Glioma Growth Human Hypersensitivity In Vitro Lead Malignant Neoplasms Maps Measures Metastatic malignant neoplasm to brain Modeling Molecular Natural Products Oncology Oxidoreductase Parents Penetrance Pharmaceutical Preparations Plasma Pre-Clinical Model Primary Brain Neoplasms Prodrugs Property Proteome Reaction Resistance Safety Series Site Solubility Structure Sulfhydryl Compounds Therapeutic Therapeutic Uses Toxic effect Toxicology Translating Treatment Efficacy Tumor Cell Line Tumor Tissue Ursidae Family Variant activity-based protein profiling aggressive breast cancer amino group analog antitumor drug cancer cell cancer therapy clinical candidate clinical investigation cytotoxicity design drug candidate human disease improved in vivo innovation malignant breast neoplasm member novel novel strategies novel therapeutics patient population physical property targeted treatment tool tumor tumor microenvironment tumor progression tumor specificity yatakemycin

项目摘要

The design, synthesis, and evaluation of a unique class of reductively activated N-acyl O-aminophenol prodrug analogues of the duocarmycins are investigated to ultimately improve cancer therapy. Studies to date demonstrate that: (1) the N-acyl O-aminophenol prodrugs release the free drug in vitro providing derivatives that approach the potency of the parent free drug, (2) this reactivity may be finely tuned by changing both the electron-withdrawing character (reactivity: R = NHCOR > NHCO2R > NMeCO2R > NHCONH2) and steric environment surrounding the amino group, (3) these reactivity differences translate into a remarkable range of prodrug stabilities and propensities for N–O bond cleavage even with subtle variations in the electronic and steric parameters, (4) there are clear predictable correlations between ease of cleavage, in vitro cytotoxicity, and in vivo potency and efficacy, and (5) that those prodrugs which exhibit a well-balanced reactivity [stability vs cleavage] also exhibit in vivo antitumor efficacies that greatly surpass those of the parent drugs. Plans are detailed to: (1) examine additional N–O prodrug designs to further define the structure-function properties, (2) analyze mechanism of in vitro and in vivo N–O bond cleavage with free drug release, and (3) comprehensively examine the most promising and advanced prodrug candidate prepared to date for its ability to inhibit progression of otherwise hard-to-treat cancers in advanced preclinical models. These studies will refine an understanding of the prodrug's in vivo behavior, provide a compelling rationale for its use in targeted therapy, and help define the tumor indication and patient populations most likely to respond to drug administration. Displaying remarkable stability in plasma, a therapeutic window of anti-tumor efficacy much larger than the free drug in a simple tumor model, slow sustained free drug release and preferential free drug release in tumor tissue versus plasma, combined with a stunning lack of bone marrow toxicity, the lead prodrug candidate will be examined in models of aggressive breast cancer and advanced metastatic disease. Addressing the most challenging unmet clinical needs, the lead prodrug will be further investigated in brain metastasis and glioma, conditions that are generally fatal and very likely to benefit from the blood brain barrier penetrance of our prodrug and its proposed ability to inhibit growth of otherwise drug-resistant cancer cells. Information and therapeutic tools from this study will enrich the field, foster development of targeted highly effective cancer drugs, and might directly enable clinical investigation of a unique new class of reductively activated duocarmycin prodrugs with unparalleled efficacy and safety to provide treatment for cancer patients with otherwise fatal conditions.

一类还原活化的N-酰基O-氨基酚的独特类型的设计，合成和评估研究了Duocarmycins的前药类似物，以最终改善癌症疗法。研究迄今为止证明：（1）N-酰基O-氨基苯酚前药在体外释放免费药物接近父母无药效力的衍生物，（2）这种反应性可能会通过更改绘制电子字符（反应性：r = nhcor> nhco2r> nmeco2r> NHCONH2）和周围氨基组的空间环境，（3）这些反应性差异翻译即使有微妙的电子和空间参数的变化，（4）之间存在明显的可预测相关性易于切割，体外细胞毒性和体内效力和效率，以及（5）那些前途表现出均衡的反应性[稳定性与裂解]也表现出体内抗肿瘤效率超过家长药物的毒品。计划详细介绍：（1）检查其他N – O前药设计进一步定义结构功能，（2）分析体外和体内N – O键的机制免费释放药物的乳沟，（3）全面检查最有前途和最先进的前药候选人迄今为止准备抑制其他难以治疗的癌症进展的能力在高级临床前模型中。这些研究将完善对前药的体内的理解行为，为靶向治疗提供了令人信服的理由，并有助于定义肿瘤适应症和患者人口最有可能对药物管理作出反应。表现出色血浆中的稳定性，抗肿瘤效率的治疗窗口比简单的自由药物大得多肿瘤模型，缓慢持续的免费药物释放，并在肿瘤组织中首选免费药物释放血浆，结合令人难以置信的缺乏骨髓毒性，铅前药候选人将是在侵略性乳腺癌和晚期转移性疾病的模型中进行了检查。解决最多的问题挑战未满足的临床需求，将在脑转移和神经胶质瘤，通常致命的疾病，很可能会从血液屏障渗透中受益我们的前药及其提议抑制其他耐药癌细胞生长的能力。这项研究的信息和治疗工具将丰富领域，促进目标的发展有效的癌症药物，并可能直接实现对独特的新类别减少的临床研究活化的Duocarmycin前药具有无与伦比的效率和安全性，可为癌症提供治疗否则致命状况的患者。