2. Academic Validation
  3. Discovery of Focal Adhesion Kinase (FAK) activators to promote intestinal mucosal healing

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

  • Eur J Med Chem. 2026 Mar 15:306:118606. doi: 10.1016/j.ejmech.2026.118606.
Ricardo Gallardo-Macias 1,  Qinggang Wang 2,  Ahmed Adham Raafat Elsayed 3,  Guiming Liu 3,  Henry L Wong 1,  Gunda I Georg 1,  Marc D Basson 4,  Vadim J Gurvich 5
Affiliations

Affiliations

  • 1 Institute for Therapeutics Discovery and Development and Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA.
  • 2 Department of Cancer Biology, MD Anderson Cancer Center, Houston, TX, USA.
  • 3 Department of Biomedical Sciences, College of Medicine, Northeast Ohio Medical University, Rootstown, OH, USA.
  • 4 Department of Biomedical Sciences, College of Medicine, Northeast Ohio Medical University, Rootstown, OH, USA. Electronic address: [email protected].
  • 5 Institute for Therapeutics Discovery and Development and Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA. Electronic address: [email protected].
PMID: 41576909 DOI: 10.1016/j.ejmech.2026.118606
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.

Keywords

Caco-2 FAK; Focal adhesion kinase; Kinase activator; Nonsteroidal anti-inflammatory drugs; Phosphorylation; Structure-activity relationship; Wound healing.

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