LFA-9 (mPGES-1/5-LOX Inhibitor): Preclinical Studies to Support a Clinical Trial,

LFA-9（mPGES-1/5-LOX 抑制剂）：支持临床试验的临床前研究，

基本信息

批准号：
10399397
负责人：
David McCormick
金额：
$ 84.42万
依托单位：
IIT RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-17 至 2021-09-16
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10399397
关键词：
APC gene Abdominal Pain Adverse effects Affect Anti-Inflammatory Agents ApcMin/+ mice Arachidonate 5-Lipoxygenase Aspirin Biological Biological Assay Canis familiaris Cardiovascular system Cells Chemoprevention Chemopreventive Agent Chronic Clinical Trials Colon Colonic Neoplasms Colorectal Cancer Coronary heart disease Development Diarrhea Disease Docking Dominant Genetic Conditions Dose Drug Kinetics Duodenum Epoprostenol Event Familial Adenomatous Polyposis Syndrome Gene Mutation Genes Head Hepatocyte Hereditary Disease High Pressure Liquid Chromatography Human Ibuprofen In Vitro Inflammatory Intestinal Neoplasms LOX gene Left Mammalian Cell Metabolism Methods Molecular Mus Mutation Naproxen Nervous System Physiology Oral Oral Administration PTGS2 gene Patients Precancerous Polyp Prostaglandin Production Prostaglandins Prostaglandins I Rattus Recording of previous events Recovery Rectum Research Personnel Risk Rodent Small Intestinal Neoplasm Techniques Testing Toxic effect Work adenoma analog appropriate dose cardiovascular risk factor celecoxib colorectal cancer prevention cyclooxygenase 1 cytokine efficacy study in silico in vivo inhibitor/antagonist lead candidate lifetime risk nonhuman primate preclinical study screening side effect targeted agent thrombotic

项目摘要

Familial Adenomatous Polyposis (FAP) is a rare inherited disease which results from an autosomal dominant genetic alteration in the adenomatous polyposis coli (APC) gene. Patients with this disease develop hundreds to thousands of pre-cancerous polyps (adenomas) in the duodenum, colon and rectum. Left untreated, patients have almost 100% lifetime risk of developing colorectal cancer (CRC). There is unequivocal evidence of chemopreventive efficacy in CRC with anti-inflammatory agents that exert their effects through COX-2 inhibition (e.g. aspirin, ibuprofen, naproxen and celecoxib), however chronic use of these agents is associated with an increased risk of GI toxicity. Moreover, agents that target COX-2 have been implicated in cardiovascular (CV) and thrombotic events for patients with a baseline history of atherosclerotic heart disease. Several investigators have shown the increased CV risk to be associated with reduced levels of prostaglandin I2 (PGI2 or prostacyclin) and increased levels of 5-lipoxygenase (5-LOX) metabolites. Hence, Dr. Rao and others hypothesize that agents that spare PGI2 and selectively block production of prostaglandin E-2 (PGE2) and 5-LOX metabolites should prove promising in the prevention of CRC. One such agent, licofelone, targets microsomal prostaglandin E Synthase-1 (mPGES-1) and 5-LOX, and suppresses small intestinal and colonic tumor formation in the ApcMin/+ mouse at doses that are devoid of overt toxicity. Inhibition of intestinal tumors was also associated with decreases in inflammatory cytokines and COX and 5-LOX activities. Furthermore, in clinical trials for OA, the common side effects with licofelone were mild (abdominal pain and diarrhea). In silico molecular docking techniques and in vitro and in vivo screening methods have been employed to identify biologically active licofelone analogs. The lead candidate of this effort, LFA- 9, has been selected for further development. The main objective of this Task Order RFP is to conduct preclinical studies with LFA-9 to support its use in a clinical trial.

家族性腺瘤性息肉病（FAP）是一种罕见的遗传疾病，它是由腺瘤息肉大肠杆菌（APC）基因的常染色体显性遗传改变引起的。这种疾病的患者在十二指肠，结肠和直肠上发展了数百至数千至数千个癌前息肉（腺瘤）。未经治疗的左病人患有几乎100％的结直肠癌（CRC）的终生风险。有明确的证据表明，CRC中具有抗炎剂的化学预防功效，通过COX-2抑制作用（例如，阿司匹林，布洛芬，萘普生和塞来昔布）发挥作用，但是这些药物的长期使用与GI毒性的风险增加有关。此外，针对COX-2的药物与动脉粥样硬化心脏病基线病史的患者有关心血管（CV）和血小板事件。几名研究人员表明，与降低前列腺素I2（PGI2或前列环素）和5-脂氧合酶（5-lox）代谢物水平降低相关的CV风险增加。因此，Rao博士和其他人假设避免PGI2并有选择地阻止Prostaglandin E-2（PGE2）和5-lox代谢物的代理人应证明有望预防CRC。一种这样的药物，licofelone，靶向微粒体前列腺素E合酶-1（MPGES-1）和5-lox，并以剂量抑制Apcmin/+小鼠中的小肠和结肠肿瘤形成，这些剂量没有明显的毒性。抑制肠道肿瘤也与炎症细胞因子和COX和5-LOX活性的降低有关。此外，在OA的临床试验中，licofelone的常见副作用轻度（腹痛和腹泻）。在计算机分子对接技术以及体外和体内筛选方法中，已采用了生物活性的氯莫酮类似物。这项工作的主要候选人是LFA-9，已被选为进一步发展。该任务顺序RFP的主要目的是使用LFA-9进行临床前研究，以支持其在临床试验中的使用。