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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.

一类独特的还原活化N-酰基邻氨基苯酚的设计、合成与鉴定研究了双霉素的前药类似物，以最终改善癌症治疗。研究结果表明：(1)N-酰基邻氨基苯酚前药体外释放游离药物提供接近母体游离药物效力的衍生物，(2)这种反应性可以通过以下方式微调改变吸电子性质(反应性：R=NHCOR&GT；NHCO2R&GT；NMeCO2R&GT； NHCONH2)和氨基周围的空间环境，(3)这些反应性差异翻译前药的稳定性和N-O键断裂倾向的显著范围，即使是微妙的电子参数和空间参数的变化；(4)电子和空间参数之间存在明显的可预测的相关性易于切割，体外细胞毒性，体内效力和疗效，和(5)那些前药，表现出平衡的反应性[稳定性与裂解]在体内也表现出极大的抗肿瘤效果超过母体药物。详细的计划是：(1)审查额外的N-O前药设计，以进一步明确了N-O键的结构-功能性质；(2)分析了N-O键的体内外形成机制卵裂与自由药物释放，以及(3)全面考察最有前途和最先进的前药候选药物因其抑制难以治疗的癌症进展的能力而备受关注在先进的临床前模型中。这些研究将加深对前药在体内的理解行为，为其在靶向治疗中的使用提供了令人信服的理由，并有助于确定肿瘤适应症和患者群体最有可能对药物管理做出反应。展现非凡的一面在血浆稳定性方面，抗肿瘤治疗窗的疗效远大于游离药物中的简单肿瘤模型、肿瘤组织缓释药物和优先释放药物与血浆，再加上令人震惊的缺乏骨髓毒性，领先的前药候选将是在侵袭性乳腺癌和晚期转移性疾病的模型中进行检查。解决最多的挑战未得到满足的临床需求，前导药物将在脑转移瘤和脑转移瘤中进一步研究神经胶质瘤，通常是致命的，很可能受益于血脑屏障的穿透。我们的前药及其所提出的抑制耐药癌细胞生长的能力。来自这项研究的信息和治疗工具将丰富该领域，促进高度针对性的发展有效的抗癌药物，并可能直接使临床研究成为一种独特的新型还原药物具有无可比拟的疗效和安全性的活性多卡霉素前体药物为癌症提供治疗患有其他致命疾病的患者。