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:
    10794912
  • 负责人:
  • 金额:
    $ 41.87万
  • 依托单位:
  • 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 2024-03-16
  • 项目状态:
    已结题

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)是一种罕见的遗传性疾病,由结肠腺瘤性息肉病(APC)基因的常染色体显性遗传改变引起。这种疾病的患者会在十二指肠、结肠和直肠形成成百上千的癌前息肉(腺瘤)。如果不进行治疗,患者几乎有100%的终身风险发展为结直肠癌(CRC)。 有明确的证据表明,使用通过抑制COX-2发挥作用的抗炎药(如阿司匹林、布洛芬、萘普生和塞来昔布)对结直肠癌具有化学预防效果,但长期使用这些药物会增加胃肠道毒性的风险。此外,针对COX-2的药物已经被认为与有动脉粥样硬化性心脏病基线病史的患者的心血管(CV)和血栓事件有关。 一些研究人员已经证明,心血管风险的增加与前列腺素I2(PGI2或前列环素)水平降低和5-脂氧合酶(5-LOX)代谢产物水平增加有关。因此,Rao博士和其他人假设,避免PGI2并选择性阻止前列腺素E-2(PGE2)和5-LOX代谢物产生的药物在预防结直肠癌方面应该被证明是有前途的。其中一种药物,利福酮,靶向微粒体前列腺素E合成酶-1(mPGES-1)和5-LOX,并以无明显毒性的剂量抑制ApcMin/+小鼠的小肠和结肠肿瘤的形成。肠道肿瘤的抑制还与炎性细胞因子、COX和5-LOX活性的降低有关。此外,在骨性关节炎的临床试验中,利福酮的常见副作用 症状轻微(腹痛和腹泻)。 在电子计算机中,分子对接技术和体外和体内筛选方法已被用于鉴定具有生物活性的利福酮类似物。这项工作的主要候选者LFA-9已被选定作进一步开发。该任务单RFP的主要目标是进行LFA-9的临床前研究,以支持其在临床试验中的使用。

项目成果

期刊论文数量(0)
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David McCormick其他文献

David McCormick的其他文献

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{{ truncateString('David McCormick', 18)}}的其他基金

Brain States and Flexible Behavior
大脑状态和灵活行为
  • 批准号:
    10700739
  • 财政年份:
    2020
  • 资助金额:
    $ 41.87万
  • 项目类别:
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,
  • 批准号:
    10399397
  • 财政年份:
    2018
  • 资助金额:
    $ 41.87万
  • 项目类别:
IGF::OT::IGF NExT Preclinical Toxicology & Pharmacology of Drugs Developed for Cancer Patients, TO#3, Exploratory Studies of CCR4 CART Cells
IGF::OT::IGF NExT 临床前毒理学
  • 批准号:
    10361380
  • 财政年份:
    2017
  • 资助金额:
    $ 41.87万
  • 项目类别:
Mechanisms of Rapid Modulation of Auditory Responsiveness
听觉反应快速调节机制
  • 批准号:
    10055961
  • 财政年份:
    2016
  • 资助金额:
    $ 41.87万
  • 项目类别:
Cortical Dynamics and Neural/Behavioral Performance
皮质动力学和神经/行为表现
  • 批准号:
    10544429
  • 财政年份:
    2016
  • 资助金额:
    $ 41.87万
  • 项目类别:
Cortical Dynamics and Neural/Behavioral Performance
皮质动力学和神经/行为表现
  • 批准号:
    10530597
  • 财政年份:
    2016
  • 资助金额:
    $ 41.87万
  • 项目类别:
Cortical Dynamics and Neural/Behavioral Performance
皮质动力学和神经/行为表现
  • 批准号:
    10058278
  • 财政年份:
    2016
  • 资助金额:
    $ 41.87万
  • 项目类别:
Cortical Dynamics and Neural/Behavioral Performance
皮质动力学和神经/行为表现
  • 批准号:
    10304870
  • 财政年份:
    2016
  • 资助金额:
    $ 41.87万
  • 项目类别:
CALCIUM SIGNALING AND PREFRONTAL DEFICITS IN SCHIZOPHRENIA
精神分裂症的钙信号传导和前额叶缺陷
  • 批准号:
    7958212
  • 财政年份:
    2009
  • 资助金额:
    $ 41.87万
  • 项目类别:
Properties of Axons and Synaptic Communication in the Neocortex
新皮质中轴突和突触通讯的特性
  • 批准号:
    7760193
  • 财政年份:
    2008
  • 资助金额:
    $ 41.87万
  • 项目类别:

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患有功能性腹痛疾病的青少年的睡眠结构被破坏
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针对有功能性腹痛风险的幼儿进行基于互联网的预防干预的随机对照试验
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