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![A, chemical name: N-Methyl-N-(3-{[2-(2-oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-2-yl)- methanesulfonamide; molecular formula: C 21 H 2 F 3 N 7 O 3 S . C 6 H 6 O 3 S; molecular weight: 507.50 (free base); 665.68 (besylate salt). B, the crystal structure of PF-562,271 (green ) bound to the active site of FAK (cyan ). Dashed lines, canonical backbone hydrogen bonds to Cys-502, as is the hydrogen bond between the oxindole O atom and Arg-426. Glu-506 and Asp564 are labeled for reference. Residues 428 to 435, which fold over the active site upon substrate or ligand binding, have been omitted for clarity. C, closeup view of the methyl-sulfonamide interaction with the DFG region of FAK. Orange dashed lines, hydrophobic interactions between Leu-567 and the pyridinyl moiety of PF-562,271. Note the hydrogen bond between the sulfonamide O atom and the backbone NH of Asp-564. D, a Double-Reciprocal Plot (Lineweaver-Burke) of velocity versus ATP concentration (50 to 200 mmol/L) at varying PF-562,271 concentrations (1 pmol/L to 9 nmol/L) demonstrating competitive inhibition. PF-562,271 competitively inhibits FAK at equivalent V max rates over the concentration range tested: VM, ATP = 0.059 nmol/L min; VM, 1 pmol/L = 0.060 pmol/L min; VM, 1 nmol/L = 0.049 nmol/L min; VM, 3 nmol/L = 0.037 nmol/L min; and VM, 9 nmol/L = 0.032 nmol/L min.](profile/Felix-Vajdos/publication/5512220/figure/fig1/AS:339851414130706@1458038299823/A-chemical-name.png)
A, chemical name: N-Methyl-N-(3-{[2-(2-oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-2-yl)- methanesulfonamide; molecular formula: C 21 H 2 F 3 N 7 O 3 S . C 6 H 6 O 3 S; molecular weight: 507.50 (free base); 665.68 (besylate salt). B, the crystal structure of PF-562,271 (green ) bound to the active site of FAK (cyan ). Dashed lines, canonical backbone hydrogen bonds to Cys-502, as is the hydrogen bond between the oxindole O atom and Arg-426. Glu-506 and Asp564 are labeled for reference. Residues 428 to 435, which fold over the active site upon substrate or ligand binding, have been omitted for clarity. C, closeup view of the methyl-sulfonamide interaction with the DFG region of FAK. Orange dashed lines, hydrophobic interactions between Leu-567 and the pyridinyl moiety of PF-562,271. Note the hydrogen bond between the sulfonamide O atom and the backbone NH of Asp-564. D, a Double-Reciprocal Plot (Lineweaver-Burke) of velocity versus ATP concentration (50 to 200 mmol/L) at varying PF-562,271 concentrations (1 pmol/L to 9 nmol/L) demonstrating competitive inhibition. PF-562,271 competitively inhibits FAK at equivalent V max rates over the concentration range tested: VM, ATP = 0.059 nmol/L min; VM, 1 pmol/L = 0.060 pmol/L min; VM, 1 nmol/L = 0.049 nmol/L min; VM, 3 nmol/L = 0.037 nmol/L min; and VM, 9 nmol/L = 0.032 nmol/L min.
Source publication
Cancer cells are characterized by the ability to grow in an anchorage-independent manner. The activity of the nonreceptor tyrosine kinase, focal adhesion kinase (FAK), is thought to contribute to this phenotype. FAK localizes in focal adhesion plaques and has a role as a scaffolding and signaling protein for other adhesion molecules. Recent studies...
Contexts in source publication
Context 1
... and physical chemical properties. PF-562,271 is a methane sulfonamide diaminopyrimidine that is Rule of 5 compliant, demonstrating favorable physical chemical properties (Fig. 1). X-ray crystallographic analysis confirms that PF-562,271 binds in the ATP-binding cleft of FAK, forming two of the three ''canonical'' H-bonds between the inhibitor and main-chain atoms in the kinase hinge region ( Fig. 1B; for crystallographic details, see Supplementary Materials). The amino-oxindole moiety extends out from the ...
Context 2
... a methane sulfonamide diaminopyrimidine that is Rule of 5 compliant, demonstrating favorable physical chemical properties (Fig. 1). X-ray crystallographic analysis confirms that PF-562,271 binds in the ATP-binding cleft of FAK, forming two of the three ''canonical'' H-bonds between the inhibitor and main-chain atoms in the kinase hinge region ( Fig. 1B; for crystallographic details, see Supplementary Materials). The amino-oxindole moiety extends out from the active site cleft along the hinge region backbone, where the oxygen atom forms a hydrogen bond to the side chain of Arg 426. The amino-methyl pyridinyl sulfonamide group projects out from the active site toward the activation ...
Context 3
... a hydrogen bond to the side chain of Arg 426. The amino-methyl pyridinyl sulfonamide group projects out from the active site toward the activation loop region, forming interactions with residues in the '' Asp-Phe-Gly (DFG) motif '' of FAK and inducing the formation of a short stretch of a-helix including the residues around the ''DFG motif '' (Fig. 1C). The primary driver for this seems to be the favorable H-bonding interaction that is established between one of the sulfonamide oxygen atoms and the backbone NH of D564. Consistent with the fact that the FAKcd used for X-ray crystallography was uniformly nonphosphorylated (data not shown), the activation loop region of the kinase ...
Context 4
... and autophosphorylation in intact cells. PF-562,271 is a potent ATP- competitive, reversible inhibitor of FAK and Pyk2 kinase, with a IC 50 of 1.5 nmol/L (0.7 ng/mL) and 13 nmol/L (7 ng/mL), respectively (Table 1). This compound shows Michaelis-Menton kinetics, consistent with it being an ATP-competitive and reversible inhibitor of the enzyme (Fig. 1D). PF-562,271 was evaluated in a number of kinase screens and panels and displays >100Â selectivity against all tested enzymes, except for some cyclin-dependent kinase (cdk) cyclin complexes (Table 1). Although PF-562,271 was shown to be a 30-to 120-nmol/L (15.2 to 60.1 ng/mL) inhibitor of cdk2/E, cdk5/ p35, cdk1/B, and cdk3/E in ...
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Citations
... Alternatively, these insulin + /amylase + cells could be cells in transition during either β-cell to acinar or acinar to β-cell conversion. To discriminate between these possibilities, we first treated 8-week-old wild-type C57BL/6 mice with the FAK inhibitor PF562271 (FAKi), which specifically inhibits pFAK kinase activity [27][28][29][30] . The mice received FAKi treatment (50 mg/kg) or vehicle via oral gavage twice a day for 3 weeks. ...
... PF-562271 (Medkoo Biosciences, Inc., 202228) was dissolved in 5% DMSO and administered with 5% GelucireⓇ 44/14 (Gattefosse) dissolved in sterile water. PF-562271 (50 mg/kg) was given via oral gavage (20 Gauge) twice a day, as described elsewhere 28 . ...
Insufficient functional β-cell mass causes diabetes; however, an effective cell replacement therapy for curing diabetes is currently not available. Reprogramming of acinar cells toward functional insulin-producing cells would offer an abundant and autologous source of insulin-producing cells. Our lineage tracing studies along with transcriptomic characterization demonstrate that treatment of adult mice with a small molecule that specifically inhibits kinase activity of focal adhesion kinase results in trans-differentiation of a subset of peri-islet acinar cells into insulin producing β-like cells. The acinar-derived insulin-producing cells infiltrate the pre-existing endocrine islets, partially restore β-cell mass, and significantly improve glucose homeostasis in diabetic mice. These findings provide evidence that inhibition of the kinase activity of focal adhesion kinase can convert acinar cells into insulin-producing cells and could offer a promising strategy for treating diabetes.
... Integrin clustering causes FAK to be recruited to newly generated focal adhesion sites, and various downstream effectors are phosphorylated after FAK activation, resulting in angiogenesis, cell migration, and cell proliferation [16][17][18][19]. Moreover, increased FAK protein levels have been reported in cancers derived from many tissues and in tumor cell lines, while FAK expression is undetectable or low in benign neoplasms and normal tissues [20][21][22][23][24][25]. While recent studies have confirmed FAK's involvement in tumor invasion and metastasis, the underlying mechanism by which FAK influences tumor cell EMT remains unclear. ...
Background
Abnormal activation of FAK is associated with tumor development and metastasis. Through interactions with other intracellular signalling molecules, FAK influences cytoskeletal remodelling, modulation of adhesion signalling, and activation of transcription factors, promoting migration and invasion of tumor cells. However, the exact mechanism that regulates these processes remains unresolved. Herein, our findings indicate that the S-palmitoylation of FAK is crucial for both its membrane localization and activation.
Methods
The palmitoylation of FAK in U251 and T98G cells was assessed by an acyl-PEG exchange (APE) assay and a metabolic incorporation assay. Cellular palmitoylation was inhibited using 2-bromopalmitate, and the palmitoylation status and cellular localization of FAK were determined. A metabolic incorporation assay was used to identify the potential palmitoyl acyltransferase and the palmitoylation site of FAK. Cell Counting Kit-8 (CCK8) assays, colony formation assays, and Transwell assays were conducted to assess the impact of ZDHHC5 in GBM. Additionally, intracranial GBM xenografts were utilized to investigate the effects of genetically silencing ZDHHC5 on tumor growth.
Results
Inhibiting FAK palmitoylation leads to its redistribution from the membrane to the cytoplasm and a decrease in its phosphorylation. Moreover, ZDHHC5, a protein-acyl-transferase (PAT), catalyzes this key modification of FAK at C456. Knockdown of ZDHHC5 abrogates the S-palmitoylation and membrane distribution of FAK and impairs cell proliferation, invasion, and epithelial-mesenchymal transition (EMT). Taken together, our research reveals the crucial role of ZDHHC5 as a PAT responsible for FAK S-palmitoylation, membrane localization, and activation.
Conclusions
These results imply that targeting the ZDHHC5/FAK axis has the potential to be a promising strategy for therapeutic interventions for glioblastoma (GBM).
... There has been less research on the potential applications of PTK2 and theβ-catenin pathway in cancer therapies. A few preclinical and clinical trials (I, Ib, or II) have shown that PTK2 inhibitors could enhance activity in combination with cytotoxic drugs or agents targeting angiogenesis [65,[70][71][72]. Zhai and colleagues reported that APG-2449, a novel ALK/ROS1/FAK inhibitor, is effective against human ovarian tumor either alone or in combination with other therapies [73]. ...
As a common malignant tumor among women, ovarian cancer poses a serious threat to their health. This study demonstrates that long non-coding RNA NRSN2-AS1 is over-expressed in ovarian cancer tissues using patient sample and tissue microarrays. In addition, NRSN2-AS1 is shown to promote ovarian cancer cell proliferation and metastasis both in vitro and in vivo. Mechanistically, NRSN2-AS1 stabilizes protein tyrosine kinase 2 (PTK2) to activate the β-catenin pathway via repressing MG-53-mediated ubiquitinated degradation of PTK2, thereby facilitating ovarian cancer progression. Rescue experiments verify the function of the NRSN2-AS1/PTK2/β-catenin axis and the effects of MG53 on this axis in ovarian cancer cells. In conclusion, this study demonstrates the key role of the NRSN2-AS1/PTK2/β-catenin axis for the first time and explores its potential clinical applications in ovarian cancer.
... However, direct mitochondrial inhibition failed to induce PCa cell dormancy. To identify a drug that mimics PCa cell dormancy in vitro, we used a novel drug prediction artificial intelligence (AI) platform and predicted PF-562,271 (PF-271), a potent ATP-competitive and reversible focal adhesion kinase (FAK) inhibitor [31][32][33]. We validated the dormancy-mimicking effect of PF-271 by inhibiting FAK phosphorylation and inducing FAK nuclear translocation in vitro. ...
... PF-271 is a reversible and ATP-competitive inhibitor of focal adhesion kinase (FAK) [31][32][33]. We showed that PF-271 inhibited cell C4-2B proliferation in a dosedependent manner (Fig. 5B), induced G0/G1 arrest (Fig. 5C), increased NR2F1 expression at both mRNA and protein levels, decreased Ki67 and cyclin D1 mRNA expression (Fig. 5D&E), but had no effect on apoptosis (Fig. 5F). ...
Background:
Disseminated tumor cells (DTCs) can enter a dormant state and cause no symptoms in cancer patients. On the other hand, the dormant DTCs can reactivate and cause metastases progression and lethal relapses. In prostate cancer (PCa), relapse can happen after curative treatments such as primary tumor removal. The impact of surgical removal on PCa dissemination and dormancy remains elusive. Furthermore, as dormant DTCs are asymptomatic, dormancy-induction can be an operational cure for preventing metastases and relapse of PCa patients.
Methods:
We used a PCa subcutaneous xenograft model and species-specific PCR to survey the DTCs in various organs at different time points of tumor growth and in response to tumor removal. We developed in vitro 2D and 3D co-culture models to recapitulate the dormant DTCs in the bone microenvironment. Proliferation assays, fluorescent cell cycle reporter, qRT-PCR, and Western Blot were used to characterize the dormancy phenotype. We performed RNA sequencing to determine the dormancy signature of PCa. A drug repurposing algorithm was applied to predict dormancy-inducing drugs and a top candidate was validated for the efficacy and the mechanism of dormancy induction.
Results:
We found DTCs in almost all mouse organs examined, including bones, at week 2 post-tumor cell injections. Surgical removal of the primary tumor reduced the overall DTC abundance, but the DTCs were enriched only in the bones. We found that osteoblasts, but not other cells of the bones, induced PCa cell dormancy. RNA-Seq revealed the suppression of mitochondrial-related biological processes in osteoblast-induced dormant PCa cells. Importantly, the mitochondrial-related biological processes were found up-regulated in both circulating tumor cells and bone metastases from PCa patients' data. We predicted and validated the dormancy-mimicking effect of PF-562,271 (PF-271), an inhibitor of focal adhesion kinase (FAK) in vitro. Decreased FAK phosphorylation and increased nuclear translocation were found in both co-cultured and PF-271-treated C4-2B cells, suggesting that FAK plays a key role in osteoblast-induced PCa dormancy.
Conclusions:
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.
... Co-targeting this pathway using the FAK inhibitor PF562271 and the BRAF inhibitor vemurafenib could represent a promising therapeutic approach for BRAFmutant colorectal cancer (CRC) patients, as they exhibit synergistic antitumor effects in vitro and in vivo [147]. Notably, the combination of small-molecule inhibitors of β-catenin or FAK along with vemurafenib not only inhibits the proliferation of BRAF V600E colon cancer cells Colon cancer + + [175] Breast cancer + + [175] Pancreatic cancer + + [112,175] Prostate cancer + + [175][176][177] Lung cancer + + [175,178] Hepatocellular cancer + + [179] Thyroid tumor + + [180] B16 − + [181] Ovarian cancer + + [182] Ewing sarcoma + + [183] VS-6063 Defactinib, PF-04554878 FAK, Pyk2 ...
... Co-targeting this pathway using the FAK inhibitor PF562271 and the BRAF inhibitor vemurafenib could represent a promising therapeutic approach for BRAFmutant colorectal cancer (CRC) patients, as they exhibit synergistic antitumor effects in vitro and in vivo [147]. Notably, the combination of small-molecule inhibitors of β-catenin or FAK along with vemurafenib not only inhibits the proliferation of BRAF V600E colon cancer cells Colon cancer + + [175] Breast cancer + + [175] Pancreatic cancer + + [112,175] Prostate cancer + + [175][176][177] Lung cancer + + [175,178] Hepatocellular cancer + + [179] Thyroid tumor + + [180] B16 − + [181] Ovarian cancer + + [182] Ewing sarcoma + + [183] VS-6063 Defactinib, PF-04554878 FAK, Pyk2 ...
... Co-targeting this pathway using the FAK inhibitor PF562271 and the BRAF inhibitor vemurafenib could represent a promising therapeutic approach for BRAFmutant colorectal cancer (CRC) patients, as they exhibit synergistic antitumor effects in vitro and in vivo [147]. Notably, the combination of small-molecule inhibitors of β-catenin or FAK along with vemurafenib not only inhibits the proliferation of BRAF V600E colon cancer cells Colon cancer + + [175] Breast cancer + + [175] Pancreatic cancer + + [112,175] Prostate cancer + + [175][176][177] Lung cancer + + [175,178] Hepatocellular cancer + + [179] Thyroid tumor + + [180] B16 − + [181] Ovarian cancer + + [182] Ewing sarcoma + + [183] VS-6063 Defactinib, PF-04554878 FAK, Pyk2 ...
Focal adhesion kinase (FAK), a nonreceptor cytoplasmic tyrosine kinase, is a vital participant in primary cellular functions, such as proliferation, survival, migration, and invasion. In addition, FAK regulates cancer stem cell activities and contributes to the formation of the tumor microenvironment (TME). Importantly, increased FAK expression and activity are strongly associated with unfavorable clinical outcomes and metastatic characteristics in numerous tumors. In vitro and in vivo studies have demonstrated that modulating FAK activity by application of FAK inhibitors alone or in combination treatment regimens could be effective for cancer therapy. Based on these findings, several agents targeting FAK have been exploited in diverse preclinical tumor models. This article briefly describes the structure and function of FAK, as well as research progress on FAK inhibitors in combination therapies. We also discuss the challenges and future directions regarding anti-FAK combination therapies.
... In this study, we identified activation of Pyk2 and FAK signaling without modulation in the basal expression levels of total Pyk2 and FAK in tumors regrown after surgical resection, compared with primary implanted tumors (Figure 1). Pyk2 and FAK are directly involved in the regulation of glioma cell proliferation and invasion, and they can contribute to the growth of recurrent tumors [35,36] and to overall survival probability, as presented in Figure 2. ...
... Beginning two days before the tumor resection and continuing throughout the postsurgical period, the animals received treatment through oral gavage without interruption: vehicle (100 µL of PBS) or PF-562271 (50 mg/kg daily), administered twice per day. This specific dose of PF-562271 was previously established as the optimal oral dosage for mice in effectively inhibiting FAK and Pyk2 within tumors [36,39]. No adverse effects, such as weight loss, abnormal posture, or bleeding, were observed at the provided concentration of PF-562271. ...
The majority of glioblastomas (GBMs) recur shortly after tumor resection and recurrent tumors differ significantly from newly diagnosed GBMs, phenotypically and genetically. In this study, using a Gl261-C57Bl/6 mouse glioma implantation model, we identified significant upregulation of proline-rich tyrosine kinase Pyk2 and focal adhesion kinase (FAK) phosphorylation levels—pPyk2 (579/580) and pFAK (925)—without significant modifications in total Pyk2 and FAK protein expression in tumors regrown after surgical resection, compared with primary implanted tumors. Previously, we demonstrated that Pyk2 and FAK are involved in the regulation of tumor cell invasion and proliferation and are associated with reduced overall survival. We hypothesized that the use of inhibitors of Pyk2/FAK in the postsurgical period may reduce the growth of recurrent tumors. Using Western blot analysis and confocal immunofluorescence approaches, we demonstrated upregulation of Cyclin D1 and the Ki67 proliferation index in tumors regrown after resection, compared with primary implanted tumors. 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.
... Analysis of GPD1L mRNA levels in 17 hepatocellular carcinoma (HCC) cell lines in the GDSC1 database revealed a robust inverse correlation with therapeutic response, as measured by the half-maximal inhibitory concentration (IC50), for three therapeutic agents including PF-562271, Linsitinib, and BMS-754807 ( Figure 4A,B). PF-562271 is an inhibitor that targets focal adhesion kinase (FAK), a key signalling protein involved in cell adhesion, migration, and invasion [16]. Linsitinib and BMS-754807 are inhibitors that target the insulin-like growth factor 1 receptor (IGF1R), a receptor tyrosine kinase involved in cell growth and survival-signalling pathways [17,18]. ...
Hepatocellular carcinoma (HCC) is a major cause of cancer-related deaths worldwide. GPD1L, a member of the glycerol-3-phosphate dehydrogenase family, has emerged as a potential tumour suppressor gene, with high expression associated with a favourable prognosis in various cancers. Despite an intriguing inverse relationship observed with HCC, the precise role and underlying function of GPD1L in HCC remain poorly understood. Here, we aimed to investigate the prognostic significance, molecular characteristics, and predictive potential of GPD1L overexpression in HCC. Analysis of independent datasets revealed a significant correlation between high GPD1L expression and poor survival in HCC patients. Spatial and single cell transcriptome datasets confirmed elevated GDP1L expression in tumour tissue compared to adjacent normal tissue. GPD1L exhibited increased expression and promoter demethylation with advancing tumour stage, confirming positive selection during tumorigeneses. GPD1L overexpression was associated with metabolic dysregulation and enrichment of gene sets related to cell cycle control, epithelial-mesenchymal transition, and E2F targets. 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.
... Blocking FAK by PF-562,271 resulted in decreased global free [Ca 2+ ] i responses after TCR stimulation in primary murine T cells on either PLL or collagen IV coatings, supporting the hypothesis that adhesion may sensitize the T cell by producing infrequent local ADCMs. Although PF-562,271 is a commonly used FAK inhibitor with a median inhibitory concentration (IC 50 ) value of 1.5 nM for FAK, it also inhibits Pyk2 (IC 50 value = 13 nM) and Fyn (IC 50 value = 277 nM) in vitro (37). However, in intact cells, 5 to 25 μM PF-562,271 applied for up to 24 hours result in altered cell migration and FAK phosphorylation in human embryonal rhabdomyosarcoma cells (38). ...
During an immune response, T cells migrate from blood vessel walls into inflamed tissues by migrating across the endothelium and through extracellular matrix (ECM). Integrins facilitate T cell binding to endothelial cells and ECM proteins. Here, we report that Ca2+ microdomains observed in the absence of T cell receptor (TCR)/CD3 stimulation are initial signaling events triggered by adhesion to ECM proteins that increase the sensitivity of primary murine T cells to activation. Adhesion to the ECM proteins collagen IV and laminin-1 increased the number of Ca2+ microdomains in a manner dependent on the kinase FAK, phospholipase C (PLC), and all three inositol 1,4,5-trisphosphate receptor (IP3R) subtypes and promoted the nuclear translocation of the transcription factor NFAT-1. Mathematical modeling predicted that the formation of adhesion-dependent Ca2+ microdomains required the concerted activity of two to six IP3Rs and ORAI1 channels to achieve the increase in the Ca2+ concentration in the ER-plasma membrane junction that was observed experimentally and that required SOCE. Further, adhesion-dependent Ca2+ microdomains were important for the magnitude of the TCR-induced activation of T cells on collagen IV as assessed by the global Ca2+ response and NFAT-1 nuclear translocation. Thus, adhesion to collagen IV and laminin-1 sensitizes T cells through a mechanism involving the formation of Ca2+ microdomains, and blocking this low-level sensitization decreases T cell activation upon TCR engagement.
... Several FAK inhibitors are available, and some are in clinical trials (13). PF-562271 reduces FAK phosphorylation and inhibits tumour growth in vivo (14). In a mouse model of pancreatic ductal adenocarcinoma, PF-562271 inhibited tumour growth, invasion, and metastasis (15). ...
Background
Transfusion-related acute lung injury (TRALI) is a specific form of acute lung injury (ALI) that can cause complications such as respiratory distress, hypoxia, fever, and tachycardia in patients. In some cases, symptoms can develop within 6 h of a transfusion, and chest X-rays may reveal bilateral lung opacity. A study using mice found that the focal adhesion kinase (FAK) inhibitor PF-562271 improved ALI.
Methods
For the study, male BALB/Cmice aged 6–8 weeks were randomly assigned to four groups: a blank control group, a group injected with lipopolysaccharide (LPS), a group injected with LPS and 5-day stored platelets (TRALI mouse model), and a group treated with the FAK inhibitor. Pathological changes in the lung tissue, lung wet/dry weight ratio, myeloperoxidase (MPO) activity, and the expression of TNF-α, IL-6, IL-8, and FAK protein were analyzed to determine the effects of the FAK inhibitor on TRALI in mice.
Results
Histological analysis revealed that the alveolar interstitium was filled with inflammatory cells and the alveolar septum was significantly widened in the model group. The lung wet/dry weight ratio confirmed that the pulmonary edema induced by the model group was more severe than that of the LPS group. MPO activity was higher in the TRALI group than in the LPS group. The mRNA expression of TNF-α, IL-6, IL-8, and the protein expression of FAK in the lung tissue were up-regulated. After 24 h of FAK inhibitor intervention, the pulmonary edema in TRALI mice was significantly reduced, the infiltration of inflammatory cells in lung tissue was improved, the lung function was better, and the expression of inflammatory factors was downregulated.
Conclusions
The study successfully constructed a mouse TRALI model infused with aged platelets and found that the FAK inhibitor can alleviate the lung injury caused by TRALI and increase the survival rate of TRALI. Therefore, FAK inhibitors may have potential applications in the treatment of TRALI.
... Several compounds, such as TAE-226, which is associated with apoptosis induction; PF562271; and CEP-37440, have already been shown to inhibit FAK kinase. In addition, inhibitors such as PF-271 and Y15, the mechanism of action of which involves block FAK residue Y397, are considered potential blockers of tumorigenesis in breast cancer [38][39][40][41]. The results of this work indicate a suppressive effect of TRI-BE at 10 µM on the expression of p-FAK in PC3 tumor cells. ...
Cancer is a serious health problem due to the complexity of establishing an effective treatment. The purpose of this work was to evaluate the activity of a triazaspirane as a migration and invasion inhibitor in PC3 prostatic tumor cells through a possible negative regulation of the FAK/Src signal transduction pathway and decreased secretion of metalloproteinases 2 and 9. Molecular docking analysis was performed using Moe 2008.10 software. Migration (wound-healing assay) and invasion (Boyden chamber assay) assays were performed. In addition, the Western blot technique was used to quantify protein expression, and the zymography technique was used to observe the secretion of metalloproteinases. Molecular docking showed interactions in regions of interest of the FAK and Src proteins. Moreover, the biological activity assays demonstrated an inhibitory effect on cell migration and invasion, an important suppression of metalloproteinase secretion, and a decrease in the expression of p-FAK and p-Src proteins in treated PC3 cells. Triazaspirane-type molecules have important inhibitory effects on the mechanisms associated with metastasis in PC3 tumor cells.
