التفاصيل البيبلوغرافية
| العنوان: |
A novel drug-like water-soluble small molecule Focal Adhesion Kinase (FAK) activator promotes intestinal mucosal healing |
| المؤلفون: |
Qinggang Wang, Ricardo Gallardo-Macias, Emilie E. Vomhof-DeKrey, Rashmi Gupta, Svetlana A. Golovko, Mikhail Y. Golovko, Sema Oncel, Vadim J. Gurvich, Marc D. Basson |
| المصدر: |
Current Research in Pharmacology and Drug Discovery, Vol 4, Iss , Pp 100147- (2023) |
| بيانات النشر: |
Elsevier, 2023. |
| سنة النشر: |
2023 |
| المجموعة: |
LCC:Therapeutics. Pharmacology |
| مصطلحات موضوعية: |
Non-steroidal anti-inflammatory drugs, Focal adhesion kinase, Mucosal healing, Small intestine, Ulcer, Therapeutics. Pharmacology, RM1-950 |
| الوصف: |
Non-steroidal anti-inflammatory drugs (NSAIDs) injure the proximal and distal gut by different mechanisms. While many drugs reduce gastrointestinal injury, no drug directly stimulates mucosal wound healing. Focal adhesion kinase (FAK), a non-receptor tyrosine kinase, induces epithelial sheet migration.We synthesized and evaluated a water-soluble FAK-activating small molecule, M64HCl, with drug-like properties. Monolayer wound closure and Western blots measured migration and FAK phosphorylation in Caco-2 cells, in vitro kinase assays established FAK activation, and pharmacologic tests assessed drug-like properties. 30 mg/kg/day M64HCl was administered in two murine small intestine injury models for 4 days.M64HCl (0.1–1000 nM) dose-dependently increased Caco-2 FAK-Tyr 397 phosphorylation, without activating Pyk2 and accelerated Caco-2 monolayer wound closure. M64HCl dose-responsively activates the FAK kinase domain vs. the non-salt M64, increasing the Vmax of ATP-binding. Pharmacologic tests suggested M64HCl has drug-like properties and is enterally absorbed. M64HCl 25 mg/kg/day continuous infusion promoted healing of ischemic jejunal ulcers and indomethacin-induced small intestinal injury in C57Bl/6 mice. M64HCl-treated mice exhibited smaller ulcers 4 days after ischemic ulcer induction or indomethacin injury. Renal histology and plasma creatinine were normal. Mild hepatic inflammatory changes and ALT elevation were similar among M64HCl-treated mice and controls. M64HCl was concentrated in kidney and gastrointestinal mucosa and functional nephrectomy studies suggested predominantly urinary excretion. Little toxicity was observed in vitro or in single-dose mouse toxicity studies until >1000x higher than effective concentrations. M64HCl, a water-soluble FAK activator, promotes epithelial restitution and intestinal mucosal healing and may be useful to treat gut mucosal injury. |
| نوع الوثيقة: |
article |
| وصف الملف: |
electronic resource |
| اللغة: |
English |
| تدمد: |
2590-2571 |
| Relation: |
http://www.sciencedirect.com/science/article/pii/S2590257122000670; https://doaj.org/toc/2590-2571 |
| DOI: |
10.1016/j.crphar.2022.100147 |
| URL الوصول: |
https://doaj.org/article/d0e700f3f0f94c29b62d9ab5274beecb |
| رقم الانضمام: |
edsdoj.0e700f3f0f94c29b62d9ab5274beecb |
| قاعدة البيانات: |
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