Discovery of Focal Adhesion Kinase (FAK) activators to promote intestinal mucosal healing

IF 6.7 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry Pub Date : 2026-03-15 Epub Date: 2026-01-20 DOI:10.1016/j.ejmech.2026.118606

Ricardo Gallardo-Macias , Qinggang Wang , Ahmed Adham Raafat Elsayed , Guiming Liu , Henry L. Wong , Gunda I. Georg , Marc D. Basson , Vadim J. Gurvich

{"title":"Discovery of Focal Adhesion Kinase (FAK) activators to promote intestinal mucosal healing","authors":"Ricardo Gallardo-Macias , Qinggang Wang , Ahmed Adham Raafat Elsayed , Guiming Liu , Henry L. Wong , Gunda I. Georg , Marc D. Basson , Vadim J. Gurvich","doi":"10.1016/j.ejmech.2026.118606","DOIUrl":null,"url":null,"abstract":"<div><div>Chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs) causes injuries in the gastrointestinal mucosa. Proton pump inhibitors are the most common drugs prescribed to decrease upper gastrointestinal side effects caused by NSAIDs. However, they worsen the lower GI injuries caused by NSAIDs and do not directly promote restitution of the epithelial mucosa. Focal adhesion kinase (FAK) is essential in wound healing and epithelial sheet migration, making it an attractive pharmacological target. We have designed, synthesized, and evaluated a series of novel, specific FAK activators that increase FAK phosphorylation at Tyr-397 and promote mucosal healing in a Caco-2 model. We found that novel analogs <strong>10bHCl</strong>, <strong>10kHCl,</strong> and our original lead <strong>5aHCl</strong> are preclinical candidates for further studies towards mucosal wound healing. For lead <strong>5aHCl</strong>, which had previously shown healing in a mouse model, we performed a pharmacokinetic study. There are currently no therapeutics that promote mucosal healing, and no specific FAK activators beyond our work.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"306 ","pages":"Article 118606"},"PeriodicalIF":6.7000,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"European Journal of Medicinal Chemistry","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0223523426000516","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2026/1/20 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}

引用次数: 0

Abstract

Chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs) causes injuries in the gastrointestinal mucosa. Proton pump inhibitors are the most common drugs prescribed to decrease upper gastrointestinal side effects caused by NSAIDs. However, they worsen the lower GI injuries caused by NSAIDs and do not directly promote restitution of the epithelial mucosa. Focal adhesion kinase (FAK) is essential in wound healing and epithelial sheet migration, making it an attractive pharmacological target. We have designed, synthesized, and evaluated a series of novel, specific FAK activators that increase FAK phosphorylation at Tyr-397 and promote mucosal healing in a Caco-2 model. We found that novel analogs 10bHCl, 10kHCl, and our original lead 5aHCl are preclinical candidates for further studies towards mucosal wound healing. For lead 5aHCl, which had previously shown healing in a mouse model, we performed a pharmacokinetic study. There are currently no therapeutics that promote mucosal healing, and no specific FAK activators beyond our work.

Abstract Image

查看原文本刊更多论文

发现局灶黏附激酶（FAK）激活剂促进肠黏膜愈合

长期使用非甾体抗炎药（NSAIDs）会导致胃肠道黏膜损伤。质子泵抑制剂是减少非甾体抗炎药引起的上胃肠道副作用的最常用药物。然而，它们加重了非甾体抗炎药引起的下消化道损伤，并不能直接促进上皮粘膜的恢复。局灶黏附激酶（FAK）在伤口愈合和上皮片迁移中是必不可少的，使其成为一个有吸引力的药理学靶点。在Caco-2模型中，我们设计、合成并评估了一系列新的特异性FAK激活剂，这些激活剂可以增加FAK在Tyr-397位点的磷酸化并促进粘膜愈合。我们发现新的类似物10bHCl， 10kHCl和我们最初的先导物5aHCl是进一步研究粘膜伤口愈合的临床前候选物。对于先前在小鼠模型中显示愈合的5aHCl铅，我们进行了药代动力学研究。目前还没有促进粘膜愈合的治疗方法，也没有特异性的FAK激活剂。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

European Journal of Medicinal Chemistry 化学-医药化学

CiteScore

11.70

自引率

9.00%

发文量

863

审稿时长

29 days

期刊介绍： The European Journal of Medicinal Chemistry is a global journal that publishes studies on all aspects of medicinal chemistry. It provides a medium for publication of original papers and also welcomes critical review papers. A typical paper would report on the organic synthesis, characterization and pharmacological evaluation of compounds. Other topics of interest are drug design, QSAR, molecular modeling, drug-receptor interactions, molecular aspects of drug metabolism, prodrug synthesis and drug targeting. The journal expects manuscripts to present the rational for a study, provide insight into the design of compounds or understanding of mechanism, or clarify the targets.