A Unique Class of Reductively Activated Oncology Drugs

一类独特的还原激活肿瘤药物

• 批准号: 9311686
• 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
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-14 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9311686
• 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 Antibiotic; 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; 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; 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; oncology; patient population; physical property; resistance mechanism; targeted treatment; tool; tumor; tumor microenvironment; tumor progression; tumor specificity; yatakemycin

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 O-氨基苯酚的设计、合成和评估 研究了多卡霉素的前药类似物以最终改善癌症治疗。研究 迄今为止证明：（1）N-酰基O-氨基苯酚前药在体外释放游离药物，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进行微调 改变吸电子特性（反应性：R = NHCOR > NHCO2R > NMeCO2R > NHCONH2) 和氨基周围的空间环境，(3) 这些反应性差异转化为 进入一系列显着的前药稳定性和 N-O 键断裂倾向，即使是微妙的 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 裂解的容易程度、体外细胞毒性以及体内效力和功效，以及（5）那些前药 表现出良好平衡的反应性[稳定性与裂解] 还表现出极大的体内抗肿瘤功效 优于母药。计划的详细内容是：(1) 检查额外的 N-O 前药设计，以 进一步明确结构-功能特性，（2）分析体外和体内N-O键的机理 游离药物释放的裂解，以及（3）全面检查最有前途和最先进的 迄今为止已准备好的前药候选物，因其能够抑制其他难以治疗的癌症的进展 在先进的临床前模型中。这些研究将加深对前药体内作用的了解 行为，为其在靶向治疗中的使用提供令人信服的理由，并帮助定义肿瘤 最有可能对药物治疗产生反应的适应症和患者群体。表现出色 血浆稳定性好，抗肿瘤疗效的治疗窗口比简单的游离药物大得多 肿瘤模型、肿瘤组织中缓慢持续的游离药物释放和优先游离药物释放 血浆，加上令人惊叹的缺乏骨髓毒性，主要的前药候选者将是 在侵袭性乳腺癌和晚期转移性疾病模型中进行了检查。解决最多的 挑战未满足的临床需求，将进一步研究先导前药在脑转移和 神经胶质瘤，通常是致命的，很可能受益于血脑屏障的渗透性 我们的前药及其抑制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该领域，促进针对性强的发展 有效的癌症药物，并可能直接使一类独特的新型还原性药物的临床研究成为可能 活化的多卡霉素前药具有无与伦比的功效和安全性，可为癌症提供治疗 患有其他致命疾病的患者。