benzesulfonate (PF-562271) / Pfizer - LARVOL DELTA

PTK2B inhibitor PF-431396 inhibits inflammatory response and apoptosis of ovarian granulosa cells by targeting AKT1 phosphorylation in premature ovarian insufficiency. (PubMed, Int Immunopharmacol) - "In this study, a rat POI model was established by intraperitoneal injection of cyclophosphamide (Cy) for 14 days...PF-431396 facilitated AKT1 phosphorylation, and the inhibitory effects of PF-431396 on GC inflammatory response and apoptosis were reversed by an AKT1 inhibitor LY294002...Additionally, it could improve Cy-induced ovarian tissue injury, inhibit inflammation and apoptosis, and elevate p-AKT1 level in ovarian tissues. Together, our results unveil that PF-431396, a PTK2B inhibitor, ameliorates ovarian dysfunction in POI through promoting AKT1 phosphorylation, suggesting that PTK2B may be a therapeutic target for POI."

Journal • Inflammation • Women's Health • PTK2B • TYK2

Identification of biomarkers associated with programmed cell death in liver ischemia-reperfusion injury: insights from machine learning frameworks and molecular docking in multiple cohorts. (PubMed, Front Med (Lausanne)) - "Finally, BMS-536924 and PF-431396 were identified as potential therapeutic agents for LIRI. This study comprehensively characterizes PCD in LIRI and identifies one core molecule, providing a new strategy for early prevention and treatment of LIRI."

Biomarker • Journal • Cardiovascular • Hepatology • Liver Failure • Reperfusion Injury • Transplantation

Pan-cancer analysis uncovered the prognostic and therapeutic value of disulfidptosis. (PubMed, NPJ Precis Oncol) - "PF-562271, EHT-1864, and IPA-3 are potential therapeutic agents targeting disulfidptosis. Collectively, this study deciphered for the first time the importance of disulfidptosis for pan-cancer and developed the DRGs Score model that can assist clinicians in accurately predicting the prognosis and guiding individualized treatment of pan-cancer patients."

Journal • Pan tumor • Genito-urinary Cancer • Kidney Cancer • Oncology • Solid Tumor

Focal adhesion kinase promotes aerobic glycolysis in hepatic stellate cells via the cyclin D1/c-Myc/MCT-1 pathway to induce liver fibrosis. (PubMed, Sci Rep) - "LX-2 cells showed diminished migration, proliferation, and aerobic glycolysis after PF562271 intervention. FAK promotes aerobic glycolysis in LX-2 cells through the cyclin D1/c-Myc/MCT-1 pathway, thereby increasing liver fibrosis."

Journal • Fibrosis • Hepatology • Immunology • Liver Cirrhosis • CCND1 • MYC • SLC16A1 • TGFB1

Design, Synthesis, and Biochemical Evaluation of Novel MLK3 Inhibitors: A Target Hopping Example. (PubMed, J Med Chem) - "In a target hopping example we started with the focal adhesion kinase (FAK) inhibitor PF-431396 (10), which shows off-target activity toward MLK3...Furthermore, we achieved a dramatic shift in selectivity from FAK to MLK3. Here we present a new chemical class of MLK3 inhibitors, including our lead compound 37 with an outstanding IC50 value of <1 nM in a biochemical MLK3 assay while simultaneously exhibiting kinome-wide selectivity."

Journal • Oncology • MAP3K11

Prognosis and immunotherapeutic implications of molecular classification of cervical cancer based on immunophenoscore-related genes. (PubMed, J Biomol Struct Dyn) - "cluster2 had higher immune cell infiltration levels and better prognosis, with greater sensitivity to Cyclopamine, Imatinib, MG-13, Paclitaxel, PHA-665752, Rapamycin, Sorafenib, Sunitinib, and VX-680. In contrast, cluster3 had higher TTN and PIK3CA mutations and greater sensitivity to AZ628, Dasatinib, Doxorubicin, HG-6-64-1, JQ12, Midostaurin, PF-562271, TAE684, and WH-4-023. In conclusion, we developed a feasible risk score model based on IPS-related genes for cervical cancer prognosis and identified potential drugs for different cervical cancer subtypes."

IO biomarker • Journal • Cervical Cancer • Oncology • Solid Tumor • PD-L2 • PIK3CA

The mechanism of L1 cell adhesion molecule interacting with protein tyrosine kinase 2 to regulate the focal adhesion kinase-growth factor receptor-bound protein 2-son of sevenless-rat sarcoma pathway in the identification and treatment of type I high-risk endometrial cancer. (PubMed, Cytojournal) - "L1CAM expression was regulated using lentiviruses designed for either overexpression or interference, and PTK2/focal adhesion kinase (FAK) signaling was inhibited with PF431396...By upregulating PTK2 and its encoded protein FAK, L1CAM was found to promote tumor progression and increase the activation of the FAK-GRB2-SOS-RAS pathway. These findings establish L1CAM and PTK2 as reference genes for poor prognostic prediction in EC and as targets for EC therapy, providing a valuable basis for distinguishing between benign and malignant endometrial conditions and justifying the necessity of targeted therapeutic approaches."

Journal • Preclinical • Endometrial Cancer • Oncology • Sarcoma • Solid Tumor • L1CAM • MMP9 • TYK2

Prognostic value of anoikis-related genes revealed using multi-omics analysis and machine learning based on lower-grade glioma features and tumor immune microenvironment. (PubMed, Heliyon) - "The high-risk group was characterized by a "cold" tumor microenvironment (TME), a lower IDH1 mutation rate (61.7 % vs. 91.4 %), a higher TP53 mutation rate (53.7 % vs. 38.9 %), and greater sensitivity to targeted therapies such as QS11 and PF-562271...The robustness of this prognostic model was further validated through internal cross-validation and across three external cohorts. The evidence from our research suggests that ARGs could potentially serve as reliable indicators for evaluating immunotherapy effectiveness and forecasting clinical results in patients with LGG."

IO biomarker • Journal • Machine learning • Brain Cancer • CNS Tumor • Glioma • Oncology • Solid Tumor • IDH1 • TP53

Prognostic model for hepatocellular carcinoma based on necroptosis-related genes and analysis of drug treatment responses. (PubMed, Heliyon) - "Notable, Bleomycin, Obatoclax. Mesylate, PF.562271, PF.02341066, QS11, X17. AAG, and Bl. D1870 exhibited significantly different sensitivities in different subtypes, providing references for clinical practice in HCC patients."

IO biomarker • Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor

Enhanced phagocytosis associated with multinucleated microglia via Pyk2 inhibition in an acute β-amyloid infusion model. (PubMed, J Neuroinflammation) - "To assess the phagocytic capacity of multinucleated microglia and its implications for brain debris clearance, we induced their formation by inhibiting Pyk2 activity using the pharmacological inhibitor PF-431396, which triggers cytokinesis regression...These results suggest that Pyk2 inhibition can modulate microglial functions, potentially reducing neuroinflammation and aiding in the clearance of neurodegenerative disease markers. This highlights Pyk2 as a promising target for therapeutic intervention in neurodegenerative diseases."

Journal • Alzheimer's Disease • CNS Disorders • Infectious Disease • Inflammation • LAMP1

Difference in Contractile Mechanisms between the Early and Sustained Components of Ionomycin-Induced Contraction in Rat Caudal Arterial Smooth Muscle. (PubMed, Biol Pharm Bull) - "On the other hand, a ROCK inhibitor, HA-1077 (3 µM), and Pyk2 inhibitors, sodium salicylate (10 mM) and PF-431396 (3 µM), suppressed only the sustained phase of ionomycin-induced contraction...Early or sustained increase of ionomycin-induced 20 kDa light chain of myosin (LC20) phosphorylation was inhibited by each inhibitor in a manner similar to the attenuation of contraction. These results indicate that the early phase of ionomycin-induced contraction is mediated by MLCK activation by [Ca2+]i elevation, whereas the sustained phase of ionomycin-induced contraction involves RhoA/ROCK activation and inhibition of myosin light chain phosphatase (MLCP) through CaM-independent Pyk2 activation by [Ca2+]i elevation."

Journal • Preclinical • MYLK • RHOA • TYK2

Schisandra chinensis Bee Pollen Extract Inhibits Proliferation and Migration of Hepatocellular Carcinoma HepG2 Cells via Ferroptosis-, Wnt-, and Focal Adhesion-Signaling Pathways. (PubMed, Drug Des Devel Ther) - "As a medicinal plant source, Schisandra chinensis bee pollen (SCBP) possesses potential pharmacological properties, such as reducing cisplatin-induced liver injury, but its anti-liver cancer effect is still rarely reported. Protein-protein interaction network analysis and RT-qPCR validation revealed SCBPE also downregulated the focal adhesion-signaling pathway, which is abrogated by PF-562271, a well-known inhibitor of FAK. This study confirmed SCBPE suppressed the cell proliferation and migration of hepatocellular carcinoma HepG2 cells, mainly through modulation of ferroptosis-, Wnt-, hepatocellular carcinoma-, and focal adhesion-signaling pathways, providing scientific data supporting adjuvant treatment of hepatocellular carcinoma using SCBP."

Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Liver Cancer • Liver Failure • Oncology • Solid Tumor

Protective effect of FAK inhibitor PF-562271 against human umbilical vein endothelial cell injury induced by aging platelets (PubMed, Nan Fang Yi Ke Da Xue Xue Bao) - "The FAK inhibitor PF-562271 alleviates endothelial cell damage induced by LPS and aging platelets by lowering cellular oxidative stress levels and reducing inflammatory responses."

Journal • Inflammation • CD31 • CXCL8 • IL6 • PECAM1 • TNFA

ACE2 improves endothelial cell function and reduces acute lung injury by downregulating FAK expression. (PubMed, Int Immunopharmacol) - "Both DIZE and the FAK inhibitor PF562271 decreased FAK/p-FAK expression in both ALI models, attenuating ALI severity in vivo and increasing barrier function and reducing monocyte adhesion in cultured ECs. Furthermore, in vivo experiments using ANG 1-7 and the MAS inhibitor A779 corroborated that DIZE-mediated ACE2 activation stimulated the activity of the ANG 1-7/MAS axis, which inhibited FAK/p-FAK expression in the mouse lung. These findings provide further evidence that activation of ACE2 in ECs may be a valuable therapeutic strategy for ALI."

Journal • Acute Lung Injury • Acute Respiratory Distress Syndrome • Infectious Disease • Inflammation • Novel Coronavirus Disease • Pulmonary Disease • Respiratory Diseases • ACE2 • ANGPT1 • PTK2

Cellular Retinoic Acid Binding Protein 2 (CRABP2), Up-regulated by HPV E6/E7, Leads to Aberrant Activation of the Integrin β1/FAK/ERK Signaling Pathway and Aggravates the Malignant Phenotypes of Cervical Cancer. (PubMed, Biochem Genet) - "Treatment with siITGB1 or a FAK inhibitor PF-562271 or an ERK inhibitor FR180204 reversed the promoting effects of CRABP2 on cell proliferation, migration, and invasion...These results suggested that HPV16 E6/E7 promoted the malignant phenotypes of cervical cancer by upregulating the expression of CRABP2. In conclusion, CRABP2, upregulated by HPV E6/E7, promoted the progression of cervical cancer through activating the Integrin β1/FAK/ERK signaling pathway via HuR."

Journal • Cervical Cancer • Oncology • Solid Tumor • CRABP2 • ITGB1

Reactive Oxygen Species-Dependent Activation of EGFR/Akt/p38 Mitogen-Activated Protein Kinase and JNK1/2/FoxO1 and AP-1 Pathways in Human Pulmonary Alveolar Epithelial Cells Leads to Up-Regulation of COX-2/PGE Induced by Silica Nanoparticles. (PubMed, Biomedicines) - "In the present study, we demonstrated that SiNPs induced COX-2 expression and PGE release, which were inhibited by pretreatment with a reactive oxygen species (ROS) scavenger (edaravone) or the inhibitors of proline-rich tyrosine kinase 2 (Pyk2, PF-431396), epidermal growth factor receptor (EGFR, AG1478), phosphatidylinositol 3-kinase (PI3K, LY294002), protein kinase B (Akt, Akt inhibitor VIII), p38 mitogen-activated protein kinase (MAPK) (p38 MAPK inhibitor VIII), c-Jun N-terminal kinases (JNK)1/2 (SP600125), Forkhead Box O1 (FoxO1, AS1842856), and activator protein 1 (AP-1, Tanshinone IIA). Finally, the COX-2/PGE axis might promote the inflammatory responses in HPAEpiCs. In conclusion, we suggested that SiNPs induced COX-2 expression accompanied by PGE synthesis mediated via ROS/Pyk2/EGFR/PI3K/Akt/p38 MAPK- and JNK1/2-dependent FoxO1 and AP-1 activation in HPAEpiCs."

Journal • Inflammation • Pneumonia • EGFR • MAPK8 • PTGS2 • TYK2

Tumor removal limits prostate cancer cell dissemination in bone and osteoblasts induce cancer cell dormancy through focal adhesion kinase. (PubMed, J Exp Clin Cancer Res) - "Our study provides the first insights into how primary tumor removal enriches PCa cell dissemination in the bones, defines a unique osteoblast-induced PCa dormancy signature, and identifies FAK as a PCa cell dormancy gatekeeper."

Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • CTCs

Prognostic and Predictive Utility of GPD1L in Human Hepatocellular Carcinoma. (PubMed, Int J Mol Sci) - "Moreover, we demonstrated an inverse correlation between GPD1L expression and therapeutic response for three therapeutic agents (PF-562271, Linsitinib, and BMS-754807), highlighting its potential as a predictive biomarker for HCC treatment outcomes. These data provide insights into the prognostic significance, molecular characteristics, and predictive potential of GPD1L in HCC."

Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Metabolic Disorders • Oncology • Solid Tumor

Pyk2/FAK Signaling Is Upregulated in Recurrent Glioblastoma Tumors in a C57BL/6/GL261 Glioma Implantation Model. (PubMed, Int J Mol Sci) - "Treatment with Pyk2/FAK inhibitor PF-562271, administered through oral gavage at 50 mg/kg daily for two weeks beginning 2 days before tumor resection, reversed Pyk2/FAK signaling upregulation in recurrent tumors, reduced tumor volume, and increased animal survival. In conclusion, the use of Pyk2/FAK inhibitors can contribute to a delay in GBM tumor regrowth after surgical resection."

Journal • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Oncology • Solid Tumor • CCND1

Pannexin 1 Modulates Angiogenic Activities of Human Endothelial Colony-Forming Cells Through IGF-1 Mechanism and Is a Marker of Senescence. (PubMed, Arterioscler Thromb Vasc Biol) - "Panx1 expression is upregulated in human ECFCs/EPCs with replication-induced senescence and during aging. Angiogenic potential of senescent ECFCs is improved by Panx1 reduction through increased IGF-1 production via activation of the FAK-ERK axis following calcium influx reduction. Our findings provide new strategies to evaluate EPC activities and rejuvenate senescent EPCs for therapeutic angiogenesis."

Journal • Cardiovascular • Oncology • CDKN2A • IGF1

A comprehensive identification of potential molecular targets and small drugs candidate for melanoma cancer using bioinformatics and network-based screening approach. (PubMed, J Biomol Struct Dyn) - "We validated four melanoma cancer drugs (Fisetin, Epicatechin Gallate, 1237586-97-8 and PF 431396) using molecular dynamics simulation with their target proteins. As a result, the results of this study may provide resources to researchers and medical professionals for the wet-lab validation of MC diagnosis, prognosis and treatments.Communicated by Ramaswamy H. Sarma."

Journal • Melanoma • Oncology • Skin Cancer • Solid Tumor • BRAF • CDK6 • CXCR4 • ERCC3 • ITGA4 • RUNX2 • SOCS3 • STAT1

Construction and validation of 3-genes hypoxia-related prognostic signature to predict the prognosis and therapeutic response of hepatocellular carcinoma patients. (PubMed, PLoS One) - "The hypoxia-related risk signature is a reliable predictive model for better clinical management of HCC patients and offers clinicians a holistic viewpoint when determining the diagnosis and course of HCC treatment."

Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • CD4 • CD86 • LAIR1 • LGALS9 • NDRG1 • TP53

FAK inhibitor PF-562271 inhibits the migration and proliferation of high-grade serous ovarian cancer cells through FAK and FAK mediated cell cycle arrest. (PubMed, Med Oncol) - "Additionally, PF-562271 treatment inhibited colony formation and induced cell senescence through G1 phase cell cycle arrest mediated DNA replication inhibition. Taken together, the findings demonstrated that FAK inhibitor PF-562271 significantly inhibits HGSOC cell adhesion, migration, and proliferation process through FAK and/or FAK mediated cell cycle arrest, and suggested that PF-562271 could serve as a potential oncotherapeutic agent for HGSOC targeting treatment."

Journal • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor • PTK2

PF-431396 hydrate inhibition of kinase phosphorylation during adherent-invasive Escherichia coli infection inhibits intra-macrophage replication and inflammatory cytokine release. (PubMed, Microbiology (Reading)) - "This reduction in intracellular bacteria resulted in a 20-fold decrease in tumour necrosis factor α secretion by cells post-AIEC infection. These data demonstrate a key role for Pyk2 in modulating AIEC intracellular replication and associated inflammation and may provide a new avenue for future therapeutic intervention in CD."

Journal • Colorectal Cancer • Crohn's disease • Gastroenterology • Gastrointestinal Cancer • Gastrointestinal Disorder • Immunology • Infectious Disease • Inflammatory Bowel Disease • Oncology • Solid Tumor • TYK2

VE-Cadherin Gene Editing Shows a Kaiso-Dependent Loss of Vasculogenic Mimicry in Uveal Melanoma Cells (ASGCT 2023) - "Abrogation of VEC phosphorylation, through FAK inhibition (PF-271), diminished complex formation and its nuclear import...Previous studies have shown that kaiso forms a complex with p120, which prevents kaiso binding to its target genes promoters such as CCDN1, and WNT 11or MMP-7 among others. Chromatin Immunoprecipitation Assays (ChIP) reveal that both FAK and VEC silencing robustly increased kaiso binding to the WNT11 and CCND1 promoters and then negatively regulated kaiso-repressor activity, which resulted in abrogation of VM in vitro.These results establish a molecular paradigm associating pVEC with VM transformation of uveal melanoma cells owing to its ability to modulate p120 nuclear localization and kaiso-dependent gene expression."

Eye Cancer • Melanoma • Oncology • Solid Tumor • Uveal Melanoma • CCND1 • CDH5 • KDR • MMP7 • WNT11