Small-Molecule Inhibitors of the c-Fes Protein-Tyrosine Kinase

Hellwig, Sabine; Miduturu, Chandra; Kanda, Shigeru; Zhang, Jianming; Filippakopoulos, P.; Salah, E.; Deng, Xianming; Choi, Hwan Geun; Zhou, Wenjun; Hur, Wooyoung; Knapp, Stefan; Gray, Nathanael S.; Smithgall, Thomas E.

doi:10.1016/j.chembiol.2012.01.020

Cited by 33 publications

(47 citation statements)

References 50 publications

(69 reference statements)

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“…Assays were performed in quadruplicate in 384-well low-volume, non-binding, black polystyrene microplates (Corning) according to the manufacturer’s instructions and as described previously (27,33,34). Briefly, the assay measures phosphorylation of the Tyr2 FRET-peptide substrate which is labeled with coumarin and fluorescein on its Nand C-terminii, respectively, which form a FRET pair.…”

Section: Methodsmentioning

confidence: 99%

A Discovery Strategy for Selective Inhibitors of c‐Src in Complex with the Focal Adhesion Kinase SH3/SH2‐binding Region

et al. 2014

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The c-Src tyrosine kinase co-operates with the focal adhesion kinase to regulate cell adhesion and motility. Focal adhesion kinase engages the regulatory SH3 and SH2 domains of c-Src, resulting in localized kinase activation that contributes to tumor cell metastasis. Using assay conditions where c-Src kinase activity required binding to a tyrosine phosphopeptide based on the focal adhesion kinase SH3-SH2 docking sequence, we screened a kinase-biased library for selective inhibitors of the Src/focal adhesion kinase peptide complex versus c-Src alone. This approach identified an aminopyrimidinyl carbamate compound, WH-4-124-2, with nanomolar inhibitory potency and fivefold selectivity for c-Src when bound to the phospho-focal adhesion kinase peptide. Molecular docking studies indicate that WH-4-124-2 may preferentially inhibit the ‘DFG-out’ conformation of the kinase active site. These findings suggest that interaction of c-Src with focal adhesion kinase induces a unique kinase domain conformation amenable to selective inhibition.

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Section: Methodsmentioning

confidence: 99%

A Discovery Strategy for Selective Inhibitors of c‐Src in Complex with the Focal Adhesion Kinase SH3/SH2‐binding Region

et al. 2014

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“…Because Fer-deficient mice have no overt phenotypes (19), it is likely to be a drugable target. It is also promising that several inhibitors of Fes kinase were recently identified and used to inhibit osteoclast differentiation (49). On the basis of their high degree of homology, it is likely that at least a subset of Fes inhibitors are also Fer inhibitors, and this will be worth testing in future using preclinical models of metastatic lung cancer and other relevant cancer models.…”

Section: Discussionmentioning

confidence: 99%

Fer Protein-Tyrosine Kinase Promotes Lung Adenocarcinoma Cell Invasion and Tumor Metastasis

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Truesdell

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et al. 2013

Molecular Cancer Research

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Epidermal growth factor receptor (EGFR) is frequently amplified or mutated in non–small cell lung cancer (NSCLC). Although Fer protein-tyrosine kinase signals downstream of EGFR, its role in NSCLC tumor progression has not been reported. Here, Fer kinase was elevated in NSCLC tumors compared to normal lung epithelium. EGFR signaling in NSCLC cells fosters rapid Fer activation and increased localization to lamellipodia. Stable silencing of Fer in H1299 lung adenocarcinoma cells (Fer KD) caused impaired EGFR-induced lamellipodia formation compared to control cells. Fer KD NSCLC cells showed reduced Vav2 tyrosine phosphorylation that was correlated with direct Fer-mediated phosphorylation of Vav2 on tyrosine-172, which was previously reported to increase the guanine nucleotide exchange factor activity of Vav2. Indeed, Fer KD cells displayed defects in Rac-GTP localization to lamellipodia, cell migration, and cell invasion in vitro. To test the role of Fer in NSCLC progression and metastasis, control and Fer KD cells were grown as subcutaneous tumors in mice. Although Fer was not required for tumor growth, Fer KD tumor-bearing mice had significantly fewer numbers of spontaneous metastases. Combined, these data demonstrate that Fer kinase is elevated in NSCLC tumors and is important for cellular invasion and metastasis. Implications: Fer protein-tyrosine kinase is a potential therapeutic target in metastatic lung cancer. Mol Cancer Res; 11(8); 952–63. ©2013 AACR.

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“…The implications of this study are that simultaneous targeting of FER together with MET may result in more effective treatment for ovarian cancer. Although no specific inhibitor of FER has been reported as yet, the recent success of inhibitor screens targeting the other family member kinase FES (Hellwig et al 2012) suggest that it may be possible to exploit this strategy in the near future.…”

Section: Discussionmentioning

confidence: 99%

HGF-independent regulation of MET and GAB1 by nonreceptor tyrosine kinase FER potentiates metastasis in ovarian cancer

et al. 2016

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Ovarian cancer cells disseminate readily within the peritoneal cavity, which promotes metastasis, and are often resistant to chemotherapy. Ovarian cancer patients tend to present with advanced disease, which also limits treatment options; consequently, new therapies are required. The oncoprotein tyrosine kinase MET, which is the receptor for hepatocyte growth factor (HGF), has been implicated in ovarian tumorigenesis and has been the subject of extensive drug development efforts. Here, we report a novel ligand-and autophosphorylation-independent activation of MET through the nonreceptor tyrosine kinase feline sarcoma-related (FER). We demonstrated that the levels of FER were elevated in ovarian cancer cell lines relative to those in immortalized normal surface epithelial cells and that suppression of FER attenuated the motility and invasive properties of these cancer cells. Furthermore, loss of FER impaired the metastasis of ovarian cancer cells in vivo. Mechanistically, we demonstrated that FER phosphorylated a signaling site in MET: Tyr1349. This enhanced activation of RAC1/PAK1 and promoted a kinaseindependent scaffolding function that led to recruitment and phosphorylation of GAB1 and the specific activation of the SHP2-ERK signaling pathway. Overall, this analysis provides new insights into signaling events that underlie metastasis in ovarian cancer cells, consistent with a prometastatic role of FER and highlighting its potential as a novel therapeutic target for metastatic ovarian cancer.

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Small-Molecule Inhibitors of the c-Fes Protein-Tyrosine Kinase

Cited by 33 publications

References 50 publications

A Discovery Strategy for Selective Inhibitors of c‐Src in Complex with the Focal Adhesion Kinase SH3/SH2‐binding Region

A Discovery Strategy for Selective Inhibitors of c‐Src in Complex with the Focal Adhesion Kinase SH3/SH2‐binding Region

Fer Protein-Tyrosine Kinase Promotes Lung Adenocarcinoma Cell Invasion and Tumor Metastasis

HGF-independent regulation of MET and GAB1 by nonreceptor tyrosine kinase FER potentiates metastasis in ovarian cancer

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