Improving chemotherapy outcomes with proprietary molecules targeting the human mi

利用针对人类心肌的专有分子改善化疗效果

• 批准号: 8714263
• 负责人: Ward Peterson
• 金额: $ 22.5万
• 依托单位: SYMBERIX, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-06 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8714263
• 关键词: Acute; Address; Adjuvant; Adverse effects; Analgesics; Anti-Inflammatory Agents; Anti-inflammatory; Bacteria; Behavior; Beta-glucuronidase; Bile fluid; Biological Availability; Biological Markers; Cancer Patient; Carboxylic Ester Hydrolases; Cattle; Cell Line; Cellular Assay; Chemicals; Colorectal Cancer; Data; Diarrhea; Dose-Limiting; Drug Kinetics; Drug toxicity; Engineering; Enzymes; Epirubicin; Evaluation; Feces; Figs - dietary; Future; Glucuronides; Goals; Health; Hemorrhagic colitis; Human; Human Microbiome; In Vitro; Infusion procedures; Intestines; Large Intestine; Lead; Life; Liver; Malignant neoplasm of pancreas; Mammalian Cell; Mediating; Medicine; Metabolism; Microbe; Mus; Oral; Outcome; Permeability; Pharmaceutical Preparations; Pharmacodynamics; Phase; Plasma; Proteins; Quality of life; Reporting; SN-38; SN-38G; Science; Small Intestines; Staging; Tamoxifen; Technology; Testing; Therapeutic; Therapeutic Effect; Time; Toxic effect; Tretinoin; Ulcer; Work; analog; base; cancer care; carboxylesterase; chemotherapeutic agent; chemotherapy; commensal microbes; cytotoxic; cytotoxicity; drug candidate; drug discovery; flavopiridol; gastrointestinal; improved; in vivo; inhibitor/antagonist; insight; irinotecan; killings; lead series; metastatic colorectal; microbial; monolayer; mouse model; novel; prevent; public health relevance; research clinical testing; screening; small molecule; success; sugar; tumor

DESCRIPTION (provided by applicant): Although non-pathogenic microbes that reside in our intestines generally provide us with numerous health and digestive benefits, a specific microfloral activity is also responsible for the severe and sometimes deadly gastrointestinal (GI) side effects of certain chemotherapeutic and pain medications. The most dangerous and well-understood example of this commensal bacteria-induced drug toxicity is the chemotherapeutic agent irinotecan (also called CPT-11), which produces frequent, intense, and dose-limiting diarrhea. The toxic effects of CPT-11 occur in the lower GI as a result of the sugar-metabolizing activity of a microbial enzyme, the bacterial ?-glucuronidase, which converts an inactive metabolite of CPT-11 into a "reactivated" cytotoxic form that damages the large intestine. The same mechanism of bacterial-mediated toxicity is responsible for ulcerations of the small intestine associated with the use of non-steroidal anti-inflammatory drugs (NSAIDs). This project aims to develop a new class of therapeutic adjuvants that selectively targets this deleterious activity of bacterial ?-glucuronidases to prevent or treat CPT-11-induced diarrhea without harming the commensal and symbiotic intestinal flora. We previously reported that oral delivery of a small molecule inhibitor (Inh-1) of this enzyme relieved the GI damage and bloody diarrhea caused by CPT-11 in mice. Inh-1 was not lethal to microbial or mammalian cells and did not block the activity of mammalian ?-glucuronidase. To further advance this technology, we propose to synthesize and characterize novel analogues of Inh-1 for potency, selectivity, and cytotoxicity in standard bacterial and mammalian protein and cellular assays. We aim to engineer new molecules to possess little or no oral bioavailability to maximize the local therapeutic effects in the gut and minimize the potential for any systemic side effects. This phase of the project aims to identify a pharmaceutically superior molecule to Inh-1 that could serve as a lead series for further optimization in the next phase of this project, ultimately with the goal of identifying a proprietary drug for future clinical testing. The use of this technology s expected to extend to other chemotherapeutics and most NSAIDs that share this same mechanism of toxicity.

描述（由申请人提供）：虽然存在于我们肠道中的非致病性微生物通常为我们提供许多健康和消化益处，但特定的微生物群活性也是某些化疗和止痛药的严重且有时致命的胃肠道（GI）副作用的原因。这种肠道细菌诱导的药物毒性的最危险和众所周知的例子是化疗药物伊立替康（也称为CPT-11），它会产生频繁，强烈和剂量限制性腹泻。CPT-11的毒性作用发生在较低的GI中，这是由于微生物酶（细菌？葡萄糖醛酸酶，其将CPT-11的无活性代谢物转化为损伤大肠的“再活化”细胞毒性形式。细菌介导的毒性的相同机制是与使用非甾体抗炎药（NSAID）相关的小肠溃疡的原因。该项目旨在开发一种新的治疗佐剂，选择性地针对这种有害的细菌活性？葡糖醛酸苷酶来预防或治疗CPT-11诱导的腹泻，而不损害肠道和共生的肠道植物群。我们以前报道过，口服这种酶的小分子抑制剂（Inh-1）减轻了CPT-11引起的小鼠胃肠道损伤和血性腹泻。Inh-1对微生物和哺乳动物细胞无致死性，也不阻断哺乳动物细胞的活性。葡萄糖醛酸酶。为了进一步推进这项技术，我们建议合成和表征新的类似物的Inh-1的效力，选择性和细胞毒性在标准的细菌和哺乳动物蛋白质和细胞测定。我们的目标是设计新的分子，使其具有很少或没有口服生物利用度，以最大限度地提高肠道局部治疗效果，并最大限度地减少任何全身副作用的可能性。该项目的这一阶段旨在确定一种药学上优于Inh-1的上级分子，该分子可作为该项目下一阶段进一步优化的先导系列，最终目标是确定一种专利药物用于未来的临床试验。这项技术的使用有望扩展到其他化疗药物和大多数具有相同毒性机制的NSAID。