PF-573228 / Pfizer - LARVOL DELTA

Osteopontin induces airway smooth muscle cells proliferation and migration by modulating FAK/Src/YAP axis. (PubMed, Int Immunopharmacol) - "Our study indicates that OPN stimulates ASMCs proliferation and migration by binding to αVβ3 and activating FAK/Src/YAP axis, suggesting that targeting this pathway might have potential value in the management of airway remodeling of asthma."

Journal • Asthma • Immunology • Pulmonary Disease • Respiratory Diseases • SPP1

RhoE down-regulation leads to enhanced cholesterol biosynthesis and sorafenib resistance in hepatocellular carcinoma. (PubMed, J Biol Chem) - "Genetic knockout of FAK or pharmacological inhibition using defactinib or PF-573228 effectively suppressed the sorafenib-induced upregulation of AKT and HMGCR...Importantly, another RAF-targeting multikinase inhibitor, regorafenib, also triggered a similar adaptive FAK-cholesterol response, suggesting that this may be a common resistance mechanism shared among RAF inhibitors...Collectively, this study systematically uncovers a new mechanism of sorafenib resistance in HCC: downregulation of RhoE drives cholesterol biosynthesis through activation of the FAK/AKT axis, thereby activating the SHH pathway and upregulating GLI1. These findings provide a strong theoretical rationale for the use of FAK inhibitors to overcome resistance and highlight the dual clinical relevance of the cholesterol biosynthesis gene signature-both as a molecular marker for predicting resistance and as a potential guide for personalized treatment strategies in HCC."

Journal • Brain Cancer • Glioma • Hepatocellular Cancer • Oncology • Solid Tumor • GLI1 • RHOA

Fibrinogen Gamma Chain Mediates Airway Inflammation and Remodeling Through the Focal Adhesion and TGF-β/Smad2 Pathways in Chronic Obstructive Pulmonary Disease. (PubMed, Lung) - "FGG contributes to airway inflammation and remodeling in COPD. Cigarette smoke enhances FGG expression and secretion in bronchial epithelium. Increased FGG promotes the release of inflammatory cytokines and EMT through the focal adhesion and TGF-β/Smad2 pathways."

Journal • Chronic Obstructive Pulmonary Disease • Fibrosis • Immunology • Inflammation • Pulmonary Disease • Respiratory Diseases • FGG • TGFB1

CPZ promotes the proliferation of gastric cancer by activating the Wnt pathway through binding with DVL2. (PubMed, Discov Oncol) - "This study highlights the potential of CPZ as a novel biomarker and prognostic predictor for GC, while also elucidating its role in GC progression. The identification of PF-573228 as a specific inhibitor of CPZ provides a basis for the development of new therapeutic strategies for GC diagnosis and intervention."

Journal • Gastric Cancer • Oncology • Solid Tumor

The role of focal adhesion kinase in bladder cancer: translation from in vitro to ex vivo human urothelial carcinomas. (PubMed, Radiol Oncol) - "To our knowledge, this is the first report demonstrating the role of FAK and its inhibition across both normal and cancerous bladder urothelial models. This study highlights the critical role of FAK in the progression of human bladder cancer and establishes a foundation for exploring FAK inhibition as a potential therapeutic approach in bladder cancer treatment."

Journal • Preclinical • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • Urothelial Cancer • CASP3 • PTK2

Focal adhesion kinase acts on the PI3K/Akt/mTOR pathway to modulate wear particle-induced autophagy in macrophages. (PubMed, Int Immunopharmacol) - "The use of inhibitors such as PF573228 could promote autophagy in macrophages to an appropriate level after prosthesis implantation, thereby preventing infection-related damage to periprosthetic tissues. Accordingly, FAK inhibitors can be developed as a novel therapeutic option for PJI."

Journal • Infectious Disease • Inflammation • Orthopedics

Cysteine-rich 61 mediates inflammation by the NF-κB/cyclooxygenase-2 pathway in RF/6A cells. (PubMed, Taiwan J Ophthalmol) - "Induction of COX-2 by Cyr61 is mediated through the activation of the integrin ανβ3, FAK, PI3K/Akt, and NF-κB pathways in RF/6A cells."

Journal • Diabetic Retinopathy • Inflammation • Retinal Disorders • CCN1 • PTGS2

Aryl hydrocarbon receptor deficiency upregulates intercellular adhesion molecule 1 in retinal pigment epithelial cells and contributes to retinal inflammation. (PubMed, Lab Invest) - "Introducing an AHR-green fluorescent protein into AHR-KO RPE cells or pre-treating the cells with pharmacological inhibitors targeting αvβ3 (cycloRGDfk), focal adhesion kinase (PF573228), phospholipase C (U73122), ERK1/2 (U0126), and NF-κB (Bay11-7082) prevented ICAM1 induction in AHR-KO RPE cells. These mice also displayed early-onset electroretinogram degeneration. Collectively, our data support the protective role of AHR in maintaining RPE cell physiology and retinal health."

Journal • Inflammation • Ocular Inflammation • Ophthalmology • AHR • ICAM1

Focal Adhesion Kinase Orchestrates GLUT4 Translocation and Glucose Uptake via Cytoskeletal Turnover in Primary Adipocytes. (PubMed, FASEB J) - "Pharmacological inhibition (PF-573228) of focal adhesion kinase suppressed the interaction of focal adhesion kinase with numerous actin-associated proteins, reduced Rac1 activity, as well as phosphorylation of the Rac1 downstream target PAK1/2, and further led to impaired GLUT4 translocation and glucose uptake. In summary, we demonstrate that focal adhesion kinase plays a key role in controlling actin remodeling, subsequent GLUT4 translocation, and ultimately glucose transport in adipocytes."

Journal • SLC2A4

Elevated interstitial flow in the cerebrospinal fluid microenvironment accelerates glioblastoma cell migration on a microfluidic chip. (PubMed, Lab Chip) - "Finally, cytoskeleton inhibitors and decreased expressions of focal adhesion proteins, such as cytochalasin D, FAK inhibitors (VS-6063 and PF-573228), and FAK siRNA, were both proved to decrease the cells' response to IF. This work not only demonstrates the effect of IF on glioblastoma cell migration, but also indicates the reliability of microfluidic chips for modeling complex physiological environments, which is expected to be further developed for drug screening."

Journal • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor

Sustained intestinal epithelial monolayer wound closure after transient application of a FAK-activating small molecule. (PubMed, PLoS One) - "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. 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."

Journal • Gastrointestinal Disorder

Apigenin and Rutaecarpine reduce the burden of cellular senescence in bone marrow stromal stem cells. (PubMed, Front Endocrinol (Lausanne)) - "Pharmacological inhibition of FAK using PF-573228 (5 μM) and TGFβ using SB505124 (1μM), diminished Apigenin- and Rutaecarpine-induced osteoblast differentiation...Our data revealed that Apigenin and Rutaecarpine enhance osteoblastic differentiation, bone formation, and reduce the age-related effects of hBMSCs. Therefore, Apigenin and Rutaecarpine cellular treatment represent a potential strategy for maintaining hBMSCs health during aging and osteoporosis."

Journal • Stroma • Musculoskeletal Diseases • Orthopedics • Osteoporosis • Rheumatology • TGFB1

Immunological Significance of Newly Discovered Urothelial Collective Migration (AUA 2024) - "While mice were under general anesthesia induced by isoflurane, we used two-photon excitation microscopy, which enables deep tissue imaging, to visualize the urothelium. Dasatinib, a Src inhibitor, and PF-573228, a focal adhesion kinase (FAK) inhibitor, were individually administered intravenously or orally. TAK-242, a Toll-like receptor 4 (TLR4) inhibitor, was administered intravenously, followed by intravesical administration... uCCM induced by immunogenic substances appeared to depend on the integrin-FAK signaling pathway. Inhibition of this migration enhanced the infection caused by uropathogenic E. coli , suggesting that it may play an immunological role against bladder infection. This immunological function may be associated with the innate immune response, possibly mediated by pattern recognition receptors, such as TLR4."

Anesthesia • Infectious Disease • TLR4

CDK4 inhibition suppresses Rab11 mediated collective cell migration in colon cancer cells (AACR 2024) - "Furthermore, when cellular FAK activity were inhibited by PF573228 and tubulin disassembly was inhibited by paclitaxel, the cell area was increased with stable attachment, however, the membrane translocation of Rab11 was not affected. This study demonstrated cell cycle inhibition in G1 phase affected Rab11 mediated collective cell migration through tubulin regulated focal adhesion turnover for cell attachment."

Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • CDH1

Inhibition of focal adhesion kinase 2 results in a macrophage polarization shift to M2 which attenuates local and systemic inflammation and reduces heterotopic ossification after polysystem extremity trauma. (PubMed, Front Immunol) - "We tested whether the continuous infusion of a FAK2 inhibitor (Defactinib, PF-573228; 6.94 µg/kg/min for 14 days) can mitigate ectopic bone formation (HO) using an established blast-related extremity injury model involving femoral fracture, quadriceps crush injury, three hours of tourniquet-induced limb ischemia, and hindlimb amputation through the fracture site. Additionally, gene expression analyses of tissue infiltrating cells resulted in a more measurable shift from an M1 inflammatory to an M2 anti-inflammatory macrophage phenotype in the FAK2 inhibitor-treated group. Our findings suggest that FAK2 inhibition may be a novel strategy to dampen trauma-induced inflammation and attenuate HO in patients at high risk as a consequence of severe musculoskeletal polytrauma."

Journal • Cardiovascular • Inflammation • Musculoskeletal Diseases • Orthopedics

Loss of MTA2-mediated downregulation of PTK7 inhibits hepatocellular carcinoma metastasis progression by modulating the FAK-MMP7 axis. (PubMed, Environ Toxicol) - "Furthermore, deactivation of FAK using siFAK or FAK inhibitor (PF-573228, PF) synergistically contributed to PTK7 knockdown-inhibited FAK activity, MMP7 expression, and the migration and invasion abilities of HCC cells. Collectively, our findings show that PTK7 mediates HCC progression by regulating the MTA2-FAK-MMP7 axis and may be a diagnostic value for HCC patients."

Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • MMP7 • MTA2 • PTK7

Obesity Augments Urinary Tract Infection Susceptibility by Activating Focal Adhesion Kinase in Kidney Intercalated Cells (KIDNEY WEEK 2023) - "These results suggest that diet-induced obesity leads to increased UTI susceptibility by activating FAK signaling in ICs. Future studies will investigate the factors regulating FAK as targets for reducing UTI risk."

Genetic Disorders • Infectious Disease • Nephrology • Obesity

BAX activation in mouse retinal ganglion cells occurs in two temporally and mechanistically distinct steps. (PubMed, Mol Neurodegener) - "A comparison between BAX activation kinetics in tissue culture cells and in cells of a complex tissue environment shows distinct differences indicating that caution should be used when translating findings from one condition to the other. RGCs exhibit both a delay between translocation and permeabilization and the ability for translocated BAX to be retrotranslocated, suggesting several stages at which intervention of the activation process could be exploited in the design of a therapeutic strategy."

Journal • Preclinical • Gene Therapies • BAX • MAP2K4 • MAPK14

Dynamic Tensile Stress Promotes Regeneration of Achilles Tendon in a Panda Rope Bridge Technique Mice Model. (PubMed, Ann Biomed Eng) - "Furthermore, blocking FAK or ERK with selective inhibitors PF573228 and U0126 resulted in obvious adverse effects on the histological structure of the regenerated Achilles tendon. In summary, this study demonstrated that dynamic tensile stress based on the PRBT could effectively promote the regeneration of the Achilles tendon, suggesting that dynamic tensile stress enhances the cell proliferation and tenogenic differentiation via the activation of the integrin/FAK/ERK signaling pathway."

Journal • Preclinical

Focal adhesion kinase activation is involved in contractile stimulation-induced detrusor muscle contraction in mice. (PubMed, Eur J Pharmacol) - "The mouse detrusor muscle strips were preincubated with PF-573228 (2 μM), latrunculin B (1 μM), or the same volume of vehicle (DMSO) for 30 min. The contractile responses to KCl (90 mM), electrical field stimulation (EFS, 2-32 Hz), or carbachol (CCh, 10-10 M) were measured...In conclusion, FAK activation involves tension development induced by contractile stimulation in the mouse detrusor muscle. This effect is likely caused by promoting actin polymerization rather than elevating MLC phosphorylation."

Journal • Preclinical

Diallyl Trisulfide, A Major Bioactive Constituent Of The Garlic, Promotes Colonic Mucosal Healing In Ulcerative Colitis Through Accelerating Focal Adhesion Assembly And Consequent Epithelial Cell Migration Via The Rab21-Integrin Β1-Fak Pathway. (PubMed, Mol Nutr Food Res) - "DATS promotes the binding of Rab21 to integrin β1 and the endocytosis of integrin β1, thereby increases FAK phosphorylation and focal adhesion assembly, finally accelerates the migration of colonic epithelial cells and mucosal healing."

Journal • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • Ulcerative Colitis

Crosstalk between protein kinases AKT and ERK1/2 in human lung tumor-derived cell models. (PubMed, Front Oncol) - "Our work showed that various and distinct inhibitors of ERK signaling - selumetinib, trametinib, and SCH772984 - increased AKT phosphorylation, and conversely, inhibitors of AKT - capivasertib, idelalisib, and AKT inhibitor VIII - increased ERK phosphorylation in both control and cisplatin-treated cells...The feedback between ERK and AKT was attenuated by the focal adhesion kinase inhibitor PF573228, and in cells grown in suspension, showing the possible role of extracellular contacts in the regulation of crosstalk between kinases. Moreover, studies have shown that the interplay between MEK/ERK and PI3K/AKT signaling pathways may be dependent on the strength of the chemotherapeutic stimulus. The study highlights the importance of spatial location of the cells and the strength of the treatment during anticancer therapy."

Journal • Lung Cancer • Oncology • Solid Tumor

Role of synaptotagmin 13 (SYT13) in promoting breast cancer and signaling pathways. (PubMed, Clin Transl Oncol) - "The results indicated that SYT13 promoted the malignant phenotypes of breast cancer cells by the activation of FAK/AKT signaling pathway."

IO biomarker • Journal • Breast Cancer • Oncology • Solid Tumor • ANXA5 • BAX • BCL2 • CCND1 • CDH1 • CDK4 • CDKN1A • VIM

Coordination of LMO7 with FAK Signaling Sustains Epithelial Integrity in Renal Epithelia Exposed to Osmotic Pressure. (PubMed, Cells) - "Conversely, FAK inhibition by PF-573228 led to failure in robust cortical F-actin assembly and LMO7 association with cortical F-actin in epithelial cells responding to hypertonic stress...LMO7 elaborately manages FAK activation in renal epithelial cells, which was demonstrated excessive FAK activation present in LMO7 depleted NRK-52E cells and epithelial integrity loss when cells with LMO7 depletion were exposed to a hypertonic environment. Our data suggests that LMO7 regulates FAK activation and is responsible for maintaining REB under osmotic disturbance."

Journal • LMO7

αEGFR-E-P125A antibody-endostatin fusion protein reduces vasculogenic mimicry and tumor cell motility by inhibition of EGFR, integrin and FAK signaling (SABCS 2022) - "Although expression of, and signaling by the epidermal growth factor receptor (EGFR) is commonly seen in TNBC, anti-EGFR antibodies such as Cetuximab have had limited therapeutic efficacy, used alone or in combination with chemotherapy...Specific inhibition of FAK at the Y397 site using the small molecule inhibitor, PF-573228 inhibited TNBC VM in vitro...These results indicate that αEGFR-E-P125A is bound to both EGFR and α5β1 integrin, simultaneously suppressing downstream EGFR and integrin signaling. Simultaneous inhibition of EGFR and α5β1integrin signaling by αEGFR-E-P125A fusion is a promising approach to inhibition of TNBC growth and metastases."

Breast Cancer • Oncology • Triple Negative Breast Cancer • CD61 • FN1 • ITGA5 • ITGB1 • KRAS • SEC23IP • STAT3