A novel drug-like water-soluble small molecule Focal Adhesion Kinase (FAK) activator promotes intestinal mucosal healing

Wang, Qinggang; Gallardo‐Macias, Ricardo; Vomhof-DeKrey, Emilie E.; Gupta, Rashmi; Golovko, Svetlana A.; Golovko, Mikhail Y.; Oncel, Sema; Gurvich, Vadim J.; Basson, Marc D.

doi:10.1016/j.crphar.2022.100147

Cited by 3 publications

(1 citation statement)

References 74 publications

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“…As an example, Panax ginseng effectively supported intestinal barrier recovery after indomethacin-induced injury by promoting the expression of transporters responsible for Ca 2+ -signaling [4 ▪ ], which is required for cell migration during restitution [5]. Likewise, a novel molecule that specifically targets focal adhesion kinase (FAK), M64HCl, was developed to activate FAK and promote wound healing, which also accelerated the repair of duodenal ulcers after treatment with indomethacin [6 ▪ ]. Studies were also done to examine intestinal barrier damage caused by professional and personal dishwasher detergents and rinse aids [7].…”

Section: Introductionmentioning

confidence: 99%

Pathophysiology updates: gastroduodenal injury and repair mechanisms

Hagen

2023

Current Opinion in Gastroenterology

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Purpose of review Although the mucosal barrier serves as a primary interface between the environment and host, little is known about the repair of acute, superficial lesions or deeper, persistent lesions that if not healed, can be the site of increased permeability to luminal antigens, inflammation, and/or neoplasia development. Recent findings Recent studies on acute superficial lesions have focused on calcium signaling and focal adhesion kinase, which regulate cell migration and controlled matrix adhesion during restitution. Microfluidic organ-on-a-chip and gut-on-a-chip models continued in development to support reductionist studies of epithelial-bacterial and/or epithelial-immune cell interactions during mucosal barrier disruption. In fact, these models may allow personalized medicine studies in the future using patient-derived cells to evaluate injury and repair mechanisms. Work done in the past year evaluated the safety and efficacy of acid blocking drugs on ulcer healing, with new animal studies providing evidence that each drug affects the microbiome in a different way that can be correlated with its efficacy in ulcer healing. Lastly, work to understand the way in which mature epithelial cells or committed stem cells dedifferentiate, reprogram, proliferate, and then regenerate the gastroduodenal mucosa after injury was a major focus of studies in the past year. Summary Recent studies highlight novel mechanisms that promote restitution and mucosal regeneration after injury of the gastroduodenal mucosa.

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Section: Introductionmentioning

confidence: 99%

Pathophysiology updates: gastroduodenal injury and repair mechanisms

Hagen

2023

Current Opinion in Gastroenterology

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Sustained intestinal epithelial monolayer wound closure after transient application of a FAK-activating small molecule

Oncel,

Wang,

Elsayed

et al. 2024

PLoS ONE

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M64HCl, which has drug-like properties, is a water-soluble Focal Adhesion Kinase (FAK) activator that promotes murine mucosal healing after ischemic or NSAID-induced injury. Since M64HCl has a short plasma half-life in vivo (less than two hours), it has been administered as a continuous infusion with osmotic minipumps in previous animal studies. However, the effects of more transient exposure to M64HCl on monolayer wound closure remained unclear. Herein, we compared the effects of shorter M64HCl treatment in vitro to continuous treatment for 24 hours on monolayer wound closure. We then investigated how long FAK activation and downstream ERK1/2 activation persist after two hours of M64HCl treatment in Caco-2 cells. M64HCl concentrations immediately after washing measured by mass spectrometry confirmed that M64HCl had been completely removed from the medium while intracellular concentrations had been reduced by 95%. Three-hour and four-hour M64HCl (100 nM) treatment promoted epithelial sheet migration over 24 hours similar to continuous 24-hour exposure. 100nM M64HCl did not increase cell number. Exposing cells twice with 2-hr exposures of M64HCl during a 24-hour period had a similar effect. Both FAK inhibitor PF-573228 (10 μM) and ERK kinase (MEK) inhibitor PD98059 (20 μM) reduced basal wound closure in the absence of M64HCl, and each completely prevented any stimulation of wound closure by M64HCl. Rho kinase inhibitor Y-27632 (20 μM) stimulated Caco-2 monolayer wound closure but no further increase was seen with M64HCl in the presence of Y-27632. M64HCl (100 nM) treatment for 3 hours stimulated Rho kinase activity. M64HCl decreased F-actin in Caco-2 cells. Furthermore, a two-hour treatment with M64HCl (100 nM) stimulated sustained FAK activation and ERK1/2 activation for up to 16 and hours 24 hours, respectively. These results suggest that transient M64HCl treatment promotes prolonged intestinal epithelial monolayer wound closure by stimulating sustained activation of the FAK/ERK1/2 pathway. Such molecules may be useful to promote gastrointestinal mucosal repair even with a relatively short half-life.

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Focal Adhesion Kinase and Colony Stimulating Factors: Intestinal Homeostasis and Innate Immunity Crosstalk

Brown,

Vomhof-DeKrey

2024

Cells

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Thousands struggle with acute and chronic intestinal injury due to various causes. Epithelial intestinal healing is dependent on phenotypic transitions to a mobile phenotype. Focal adhesion kinase (FAK) is a ubiquitous protein that is essential for cell mobility. This phenotype change is mediated by FAK activation and proves to be a promising target for pharmaceutical intervention. While FAK is crucial for intestinal healing, new evidence connects FAK with innate immunity and the importance it plays in macrophage/monocyte chemotaxis, as well as other intracellular signaling cascades. These cascades play a part in macrophage/monocyte polarization, maturation, and inflammation that is associated with intestinal injury. Colony stimulating factors (CSFs) such as macrophage colony stimulating factor (M-CSF/CSF-1) and granulocyte macrophage colony stimulating factor (GM-CSF/CSF-2) play a critical role in maintaining homeostasis within intestinal mucosa by crosstalk capabilities between macrophages and epithelial cells. The communication between these cells is imperative in orchestrating healing upon injury. Diving deeper into these connections may allow us a greater insight into the role that our immune system plays in healing, as well as a better comprehension of inflammatory diseases of the gut.

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A novel drug-like water-soluble small molecule Focal Adhesion Kinase (FAK) activator promotes intestinal mucosal healing

Cited by 3 publications

References 74 publications

Pathophysiology updates: gastroduodenal injury and repair mechanisms

Pathophysiology updates: gastroduodenal injury and repair mechanisms

Sustained intestinal epithelial monolayer wound closure after transient application of a FAK-activating small molecule

Focal Adhesion Kinase and Colony Stimulating Factors: Intestinal Homeostasis and Innate Immunity Crosstalk

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