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.

设计、合成和评价一类独特的还原活化n -酰基o -氨基苯酚