新型促进黏膜愈合的小分子黏着斑激酶激活剂的发现
Discovery of Novel Small-Molecule FAK Activators Promoting Mucosal Healing.
作者信息
Wang Qinggang, Gallardo-Macias Ricardo, Golovko Mikhail Y, Elsayed Ahmed Adham Raafat, More Shyam K, Oncel Sema, Gurvich Vadim J, Basson Marc D
机构信息
Department of Surgery, University of North Dakota School of Medicine and Health Sciences, 1301 North Columbia Road, Grand Forks, North Dakota 58201, United States.
Institute for Therapeutics Discovery and Development and Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, 717 Delaware Street SE, Minneapolis, Minnesota 55414, United States.
出版信息
ACS Med Chem Lett. 2021 Feb 16;12(3):356-364. doi: 10.1021/acsmedchemlett.0c00311. eCollection 2021 Mar 11.
Gastrointestinal mucosal wounds are common to patients injured by factors as diverse as drugs, inflammatory bowel disease, peptic ulcers, and necrotizing enterocolitis. However, although many drugs are used to ameliorate injurious factors, there is no drug available to actually stimulate mucosal wound healing. Focal adhesion kinase (FAK), a nonreceptor tyrosine kinase, induces epithelial sheet migration and wound healing, making FAK a potential pharmacological target in this regard. In our previous research, we found a lead compound with drug-like properties, ZINC40099027, which promotes FAK phosphorylation, inducing mucosal healing in murine models. Herein we describe the design and optimization of a small library of novel FAK activators based on ZINC40099027 and their applications toward human intestinal epithelial wound closure and mouse ulcer healing.
胃肠道黏膜损伤在因药物、炎症性肠病、消化性溃疡和坏死性小肠结肠炎等多种因素而受伤的患者中很常见。然而，尽管有许多药物用于改善损伤因素，但目前尚无药物可真正刺激黏膜伤口愈合。粘着斑激酶（FAK）是一种非受体酪氨酸激酶，可诱导上皮细胞片层迁移和伤口愈合，这使得FAK在这方面成为一个潜在的药理学靶点。在我们之前的研究中，我们发现了一种具有类药物特性的先导化合物ZINC40099027，它能促进FAK磷酸化，在小鼠模型中诱导黏膜愈合。在此，我们描述了基于ZINC40099027的新型FAK激活剂小型文库的设计和优化，以及它们在人类肠道上皮伤口闭合和小鼠溃疡愈合方面的应用。
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