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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、合成和评价研究了倍癌霉素的前药类似物以最终改善癌症治疗。研究迄今证明：（1）N-酰基O-氨基苯酚前药在体外释放游离药物，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进行微调：改变吸电子特性（反应性：R = NHCOR > NHCO 2 R> NMeCO 2 R> NHCONH 2）和氨基周围的空间环境，（3）这些反应性差异转化为前体药物的稳定性和N-O键断裂倾向的显著范围，甚至与细微的电子和空间参数的变化，（4）之间存在明显的可预测的相关性易于切割、体外细胞毒性和体内效力和功效，以及（5）那些表现出良好平衡的反应性[稳定性对裂解]，也表现出体内抗肿瘤功效，超过了母体药物。详细的计划是：（1）检查额外的N-O前药设计，进一步明确其结构-功能性质，（2）分析其体内、体外N-O键的作用机理裂解与游离药物释放，和（3）全面审查最有前途的和先进的迄今为止制备的前药候选物，其能够抑制难以治疗的癌症的进展先进的临床前模型。这些研究将完善前体药物在体内的理解行为，为它在靶向治疗中的应用提供了令人信服的理由，并有助于定义肿瘤适应症和最可能对药物给药有反应的患者人群。表现出色在血浆中的稳定性，抗肿瘤功效的治疗窗口远大于简单的游离药物肿瘤模型，缓慢持续的游离药物释放和优先的游离药物释放在肿瘤组织与血浆，结合惊人的缺乏骨髓毒性，领先的前药候选人将是在侵袭性乳腺癌和晚期转移性疾病的模型中进行了检查。使解决最挑战未满足的临床需求，将进一步研究该先导前药在脑转移中的作用，神经胶质瘤，通常是致命的，并且很可能受益于血脑屏障的疾病。我们的前体药物及其抑制其他耐药癌细胞生长的能力。本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癌症药物，并可能直接使临床研究的一个独特的新类别的减少，具有无与伦比的功效和安全性的活性倍癌霉素前药其他致命疾病的患者。