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

家族性腺瘤性息肉病（FAP）是一种罕见的遗传性疾病，其起因于大肠腺瘤性息肉病（APC）基因的常染色体显性遗传改变。患有这种疾病的患者在十二指肠、结肠和直肠中形成数百至数千个癌前息肉（腺瘤）。如果不进行治疗，患者几乎有100%的终身风险患结直肠癌（CRC）。 有明确的证据表明，通过抑制考克斯-2发挥作用的抗炎药（例如阿司匹林、布洛芬、萘普生和塞来昔布）对CRC具有化学预防功效，但长期使用这些药物与GI毒性风险增加相关。此外，靶向考克斯-2的药物与基线有动脉粥样硬化性心脏病病史的患者的心血管（CV）和血栓形成事件有关。 几位研究者已经证明CV风险增加与前列腺素I2（PGI 2或前列环素）水平降低和5-脂氧合酶（5-LOX）代谢产物水平升高相关。因此，Rao博士和其他人假设，节省PGI 2并选择性阻断前列腺素E-2（PGE 2）和5-LOX代谢产物产生的药物在预防CRC方面应该是有希望的。一种这样的药剂，licofelone，靶向微粒体前列腺素E合酶-1（mPGES-1）和5-LOX，并且在没有明显毒性的剂量下抑制ApcMin/+小鼠中的小肠和结肠肿瘤形成。肠肿瘤的抑制也与炎性细胞因子和考克斯和5-LOX活性的降低有关。此外，在OA的临床试验中， 轻度（腹痛和腹泻）。 计算机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卡非龙类似物。这一努力的主要候选者LFA- 9已被选定用于进一步开发。本任务指令RFP的主要目的是对LFA-9进行临床前研究，以支持其在临床试验中的使用。

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.