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

基本信息

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
项目类别：
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

项目摘要

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）：虽然驻留在我们肠道中的非病原微生物通常为我们提供许多健康和消化益处，但特定的微生物活性也会导致某些化疗药物和药物产生严重甚至有时致命的胃肠道 (GI) 副作用。止痛药。这种共生细菌引起的药物毒性最危险和最容易理解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胃肠道中，这是由于微生物酶（细菌 β-葡萄糖醛酸酶）的糖代谢活性所致，该酶将 CPT-11 的非活性代谢物转化为“重新激活”的细胞毒性形式，从而损害胃肠道大肠。细菌介导的毒性的相同机制导致与使用非甾体抗炎药（NSAID）相关的小肠溃疡。该项目旨在开发一类新型治疗佐剂，选择性地针对细菌 β-葡萄糖醛酸酶的有害活性，以预防或治疗 CPT-11 引起的腹泻，而不损害共生和共生的肠道菌群。我们之前报道过，口服该酶的小分子抑制剂（Inh-1）可以减轻 CPT-11 引起的小鼠胃肠道损伤和血性腹泻。 Inh-1对微生物或哺乳动物细胞没有致命性，并且不会阻断哺乳动物β-葡萄糖醛酸酶的活性。为了进一步推进这项技术，我们建议合成和表征 Inh-1 的新型类似物，以在标准细菌和哺乳动物蛋白质和细胞测定中提高效力、选择性和细胞毒性。我们的目标是设计具有很少或没有口服生物利用度的新分子，以最大限度地提高肠道的局部治疗效果，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 的分子，该分子可以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用于未来临床测试的专有药物。这项技术的使用预计将扩展到其他化疗药物和大多数具有相同毒性机制的非甾体抗炎药。