{"doi":"10.1016/j.crphar.2022.100147","title":"A novel drug-like water-soluble small molecule Focal Adhesion Kinase (FAK) activator promotes intestinal mucosal healing","abstract":"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.","journal":"Current Research in Pharmacology and Drug Discovery","year":2022,"id":277421,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":8,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9569,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":906096,"name":"Ricardo Gallardo‐Macias","orcid":"0009-0008-1486-8261","position":1,"is_corresponding":false},{"id":379207,"name":"Emilie E. Vomhof‐DeKrey","orcid":"0000-0003-3818-5330","position":2,"is_corresponding":false},{"id":713335,"name":"Rashmi Gupta","orcid":"0009-0004-8130-9284","position":3,"is_corresponding":false},{"id":273242,"name":"Svetlana A. Golovko","orcid":null,"position":4,"is_corresponding":false},{"id":272290,"name":"Mikhail Y. Golovko","orcid":"0000-0003-1749-3158","position":5,"is_corresponding":false},{"id":713334,"name":"Sema Oncel","orcid":"0000-0001-5551-2271","position":6,"is_corresponding":false},{"id":949002,"name":"Vadim J. Gurvich","orcid":"0000-0002-5420-1639","position":7,"is_corresponding":false},{"id":49885,"name":"Marc D. Basson","orcid":"0000-0001-9696-2789","position":8,"is_corresponding":false},{"id":713336,"name":"Qinggang Wang","orcid":"0000-0002-4200-307X","position":0,"is_corresponding":true}],"reference_count":80,"raw_metadata":null,"created_at":"2026-07-19T00:28:39.226969Z","pmid":"36632414","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}