共查询到20条相似文献,搜索用时 31 毫秒
1.
Han YM Lee SK Jeong DG Ryu SE Han DC Kim DK Kwon BM 《Bioorganic & medicinal chemistry letters》2012,22(1):323-326
Anthraquinones have been reported as phosphatase inhibitors. Therefore, anthraquinone derivatives were screened to identify a potent phosphatase inhibitor against the phosphatase of regenerating liver-3 (PRL-3). Emodin strongly inhibited phosphatase activity of PRL-3 with IC(50) values of 3.5μM and blocked PRL-3-induced tumor cell migration and invasion in a dose-dependent manner. Emodin rescued the phosphorylation of ezrin, which is a known PRL-3 substrate. The results of this study reveal that emodin is a PRL-3 inhibitor and a good lead molecule for obtaining a selective PRL-3 inhibitor. 相似文献
2.
Discovery of alpha-glucosidase inhibitors has been actively pursued with the aim to develop therapeutics for the treatment of diabetes and the other carbohydrate mediated diseases. We have been able to identify 13 novel alpha-glucosidase inhibitors by means of a computer-aided drug design protocol involving homology modeling of the target protein and the virtual screening with docking simulations under consideration of the effects of ligand solvation in the binding free energy function. Because the newly discovered inhibitors are structurally diverse and reveal a significant potency with IC(50) values lower than 50 microM, all of them can be considered for further development by structure-activity relationship studies or de novo design methods. Structural features relevant to the interactions of the newly identified inhibitors with the active site residues of alpha-glucosidase are discussed in detail. 相似文献
3.
4.
Park H Bahn YJ Jeong DG Woo EJ Kwon JS Ryu SE 《Bioorganic & medicinal chemistry letters》2008,18(20):5372-5376
Extracellular signal-regulated kinase 2 (ERK2) has become an attractive target for the development of therapeutics for the treatment of cancer. We have been able to identify eight new inhibitors of ERK2 by means of a drug design protocol involving the virtual screening with docking simulations and in vitro enzyme assay. The newly discovered inhibitors can be categorized into three structural classes and reveal a significant potency with IC(50) values ranging from 1 to 30 microM. Therefore, all of the three inhibitor scaffolds deserve further development by structure-activity relationship or de novo design methods. Structural features relevant to the stabilizations of the newly identified inhibitors in the ATP-binding site of ERK2 are discussed in detail. 相似文献
5.
Park H Hwang KY Kim YH Oh KH Lee JY Kim K 《Bioorganic & medicinal chemistry letters》2008,18(13):3711-3715
Discovery of alpha-glucosidase inhibitors has been actively pursued with the aim to develop therapeutics for the treatment of diabetes and the other carbohydrate-mediated diseases. We have identified four novel alpha-glucosidase inhibitors by means of a drug design protocol involving the structure-based virtual screening under consideration of the effects of ligand solvation in the scoring function and in vitro enzyme assay. Because the newly identified inhibitors reveal in vivo antidiabetic activity as well as a significant potency with more than 70% inhibition of the catalytic activity of alpha-glucosidase at 50 microM, all of them seem to deserve further development to discover new drugs for diabetes. Structural features relevant to the interactions of the newly identified inhibitors with the active site residues of alpha-glucosidase are discussed in detail. 相似文献
6.
Park H Choi H Hong S Kim D Oh DS Hong S 《Bioorganic & medicinal chemistry letters》2011,21(7):2021-2024
Phosphoinositide 3-kinase alpha (PI3Kα) has proved to be an attractive target for the development of therapeutics for the treatment of cancer. Herein we report a successful application of the structure-based virtual screening to identify the novel inhibitors of PI3Kα. These inhibitors have desirable physicochemical properties as a drug candidate and reveal a moderate potency with IC50 values ranging from 20 to 40 μM. Therefore, they deserve a consideration for further development by structure-activity relationship (SAR) studies to optimize the inhibitory activities. Structural features relevant to the stabilization of the newly identified inhibitors in the ATP-binding site of PI3Kα are addressed in detail. 相似文献
7.
Choi H Park HJ Shin JC Ko HS Lee JK Lee S Park H Hong S 《Bioorganic & medicinal chemistry letters》2012,22(6):2195-2199
p38 Mitogen-activated protein kinase (MAPK) has been considered to be a promising target for the development of therapeutics for various immunologic diseases. Herein we report an example for a successful application of the virtual screening with protein-ligand docking to identify the novel inhibitors of p38α MAPK. These inhibitors were screened for having desirable physicochemical properties as a drug candidate and compound 1-3 revealed a moderate inhibitory activity with IC(50) values ranging from 0.7 to 20 μM. Therefore, they deserve a consideration for further development by structure-activity relationship (SAR) studies to optimize the inhibitory activities. Structural features relevant to the stabilization of the newly identified inhibitors in the ATP-binding site of p38 MAPK are addressed in detail. 相似文献
8.
Identification of integrin alpha1 as an interacting protein of protein tyrosine phosphatase PRL-3 总被引:5,自引:0,他引:5
Peng L Jin G Wang L Guo J Meng L Shou C 《Biochemical and biophysical research communications》2006,342(1):179-183
PRL-3 is a newly identified protein tyrosine phosphatase associated with tumor metastasis. It is over-expressed in various cancers, such as colorectal cancer, gastric cancer, and ovarian cancer, and is correlated with the progression and survival of cancers. Although PRL-3 plays a causative role in promoting cancer cell invasion and metastasis, the molecular mechanism is unknown. To investigate PRL-3's roles in tumorigenesis and signal transduction pathway, we screened the human placenta brain cDNA library with the bait of PRL-3 in yeast two-hybrid system. Then we identified integrin alpha1 as a PRL-3-interacting protein for the first time, and verified this physical association with pull-down and co-immunoprecipitation assays. Furthermore, we found that PRL-3 could down-regulate the tyrosine-phosphorylation level of integrin beta1 and increased the phosphorylation level of Erk1/2. Our present discovery will provide new clues for elucidating the molecular mechanism of PRL-3 in promoting cancer invasion and metastasis. 相似文献
9.
Bai Y Luo Y Liu S Zhang L Shen K Dong Y Walls CD Quilliam LA Wells CD Cao Y Zhang ZY 《The Journal of biological chemistry》2011,286(49):42316-42324
Phosphatases of the regenerating liver (PRL) play oncogenic roles in cancer development and metastasis. Although previous studies indicate that PRL-1 promotes cell growth and migration by activating both the ERK1/2 and RhoA pathways, the mechanism by which it activates these signaling events remains unclear. We have identified a PRL-1-binding peptide (Peptide 1) that shares high sequence identity with a conserved motif in the Src homology 3 (SH3) domain of p115 Rho GTPase-activating protein (GAP). p115 RhoGAP directly binds PRL-1 in vitro and in cells via its SH3 domain. Structural analyses of the PRL-1·Peptide 1 complex revealed a novel protein-protein interaction whereby a sequence motif within the PxxP ligand-binding site of the p115 RhoGAP SH3 domain occupies a folded groove within PRL-1. This prevents the canonical interaction between the SH3 domain of p115 RhoGAP and MEKK1 and results in activation of ERK1/2. Furthermore, PRL-1 binding activates RhoA signaling by inhibiting the catalytic activity of p115 RhoGAP. The results demonstrate that PRL-1 binding to p115 RhoGAP provides a coordinated mechanism underlying ERK1/2 and RhoA activation. 相似文献
10.
Sungmin Ko Myung Kyu Lee Dongkyu Shin Hwangseo Park 《Bioorganic & medicinal chemistry》2009,17(22):7769-7774
The inhibitors of factor-inhibiting HIF-1 (FIH1) have been shown to be useful as therapeutics for the treatment of anemia. We have been able to identify eight novel FIH1 inhibitors with IC50 values ranging from 30 to 80 μM by means of the virtual screening with docking simulations under consideration of the effects of ligand solvation in the scoring function. The newly identified inhibitors are structurally diverse and have various chelating groups for the active-site ferrous ion including sulfonamide, carboxylate, N-benzo[1,2,5]oxadiazol-4-yl amide, and 2-[1,2,4]triazolo[3,4-b]][1,3,4]thiadiazol-3-yl-quinoline moieties. Each of these four structural classes has not been reported as FIH1 inhibitor, and therefore can be considered for further development by structure–activity relationship or de novo design methods. The interactions with the amino acid residues responsible for the stabilizations of the inhibitors in the active site are addressed in detail. 相似文献
11.
Garam Min Su-Kyung Lee Hye-Nan Kim Young-Min Han Rhan-Hee Lee Dae Gwin Jeong Dong Cho Han Byoung-Mog Kwon 《Bioorganic & medicinal chemistry letters》2013,23(13):3769-3774
PRL-3, phosphatase of regenerating liver-3, plays a role in cancer progression through its involvement in invasion, migration, metastasis, and angiogenesis. We synthesized rhodanine derivatives, CG-707 and BR-1, which inhibited PRL-3 enzymatic activity with IC50 values of 0.8 μM and 1.1 μM, respectively. CG-707 and BR-1 strongly inhibited the migration and invasion of PRL-3 overexpressing colon cancer cells without exhibiting cytotoxicity. The specificity of the inhibitors on PRL-3 phosphatase activity was confirmed by the phosphorylation recovery of known PRL-3 substrates such as ezrin and cytokeratin 8. The compounds selectively inhibited PRL-3 in comparison with other phosphatases, and CG-707 regulated epithelial-to-mesenchymal transition (EMT) marker proteins. The results of the present study reveal that rhodanine is a specific PRL-3 inhibitor and a good lead molecule for obtaining a selective PRL-3 inhibitor. 相似文献
12.
《Journal of molecular biology》2019,431(17):3056-3067
PRL-3 belongs to the PRL phosphatase family. Its physiological role remains unclear, but many studies have identified that PRL-3 is a marker of cancer progression and shown it to be associated with metastasis. Evidence implicating PRL-3 in various elements of the metastatic process, such as the cell cycle, survival, angiogenesis, adhesion, cytoskeleton remodeling, EMT, motility and invasion, has been reported. Furthermore, several molecules acting as direct or indirect substrates have been identified. However, this information was obtained in many different studies, and it remains difficult to see the larger picture. We therefore systematically collected the published information together and used it to develop a comprehensive signaling network map. By analyzing this network map, we were able to retrieve the signaling pathways via which PRL-3 governs the key steps of the metastatic process in cancer. In this review, we summarize current knowledge of the role of PRL-3 in cancer and the molecular mechanisms involved. We also provide the web-based open-source PRL-3 signaling network map, for use in further studies. 相似文献
13.
Choi MS Min SH Jung H Lee JD Lee TH Lee HK Yoo OJ 《Biochemical and biophysical research communications》2011,(2):1313-309
The phosphatase of regenerating liver-3 (PRL-3) is a member of protein tyrosine phosphatases and whose deregulation is implicated in tumorigenesis and metastasis of many cancers. However, the underlying mechanism by which PRL-3 is regulated is not known. In this study, we identified the peptidyl prolyl cis/trans isomerase FK506-binding protein 38 (FKBP38) as an interacting protein of PRL-3 using a yeast two-hybrid system. FKBP38 specifically binds to PRL-3 in vivo, and that the N-terminal region of FKBP38 is crucial for binding with PRL-3. FKBP38 overexpression reduces endogenous PRL-3 expression levels, whereas the depletion of FKBP38 by siRNA increases the level of PRL-3 protein. Moreover, FKBP38 promotes degradation of endogenous PRL-3 protein via protein-proteasome pathway. Furthermore, FKBP38 suppresses PRL-3-mediated p53 activity and cell proliferation. These results demonstrate that FKBP38 is a novel regulator of the oncogenic protein PRL-3 abundance and that alteration in the stability of PRL-3 can have a dramatic impact on cell proliferation. Thus, FKBP38 may play a critical role in tumorigenesis. 相似文献
14.
VRAF murine sarcoma viral oncogene homologue B1 (BRAF) kinase has been considered to be a promising therapeutic target for various human cancers. We have been able to identify 24 novel BRAF kinase inhibitors with K(d) values ranging from 0.4 to 10μM utilizing a structure-based de novo design method with the two known inhibitor scaffolds. Because these discovered inhibitors were also screened for having desirable physicochemical properties as a drug candidate, they deserve consideration for further investigation as anticancer agents. Structural features relevant to the stabilization of the newly identified inhibitors in the ATP-binding site of BRAF are discussed in detail. 相似文献
15.
Phosphatase of regenerating liver-1 (PRL-1) is a novel target for potentially treating cancer metastases. Although its specific
biochemical role in these processes has yet to be delineated, considerable evidence suggests the phosphatase activity of PRL-1
is required for promoting cancer and metastasis. PRL-1 belongs to the protein tyrosine phosphatase (PTPase) family and functions
using the CX5R consensus active site motif. Like other PTPases, PRL-1 is inhibited by oxidation at its active site Cys, however, disulfide
bond formation occurs unusually readily in wild-type PRL-1. Chemical shift assignments are available for oxidized wild type,
but numerous, substantial changes are observed in the spectra upon reduction. Because the reduced form is active, we sought
to identify a stable mutant that would resist oxidation and be useful for facilitating drug screening and development using
NMR-based assays. We present here NMR assignments for a full-length, reduced and active form of PRL-1, PRL-1-C170S-C171S,
that is well suited for this purpose. 相似文献
16.
Hwanho Choi Youngseop Lee Hwangseo Park Dal-Seok Oh 《Bioorganic & medicinal chemistry letters》2010,20(21):6195-6198
Tumor necrosis factor alpha (TNF-α) has been considered as one of the attractive drug targets for allergic diseases including asthma. We have been able to identify five novel TNF-α inhibitors with a drug-design protocol involving the structure-based virtual screening and in vitro cell-based assay for antagonistic activity. Because the newly discovered inhibitors are structurally diverse and have the desirable physicochemical properties as a drug candidate, they deserve a further investigation as anti-asthmatic drugs. The interactions of the identified inhibitors in the binding site of TNF-α dimer are addressed in detail to understand the mechanisms for the stabilization of the inactive dimeric form of TNF-α. 相似文献
17.
Park H Kim SY Kyung A Yoon TS Ryu SE Jeong DG 《Bioorganic & medicinal chemistry letters》2012,22(2):1271-1275
Dual-specificity protein tyrosine phosphatase localized to mitochondrion 1 (PTPMT1) has recently proved to be a promising therapeutic target for the treatment of type II diabetes. Herein we report the first example for a successful application of the structure-based virtual screening to identify the novel inhibitors of human PTPMT1. These inhibitors were computationally screened for having desirable physicochemical properties as a drug candidate and reveal a high potency with IC(50) values ranging from 0.7 to 17.3μM. Therefore, they deserve consideration for further development by structure-activity relationship studies to optimize the antidiabetic activities. Structural features relevant to the stabilization of the newly identified inhibitors in the active site of PTPMT1 are addressed in detail. 相似文献
18.
Hyun Lee Tian Zhu Kavankumar Patel Yan-Yan Zhang Lena Truong Kirk E. Hevener Joseph L. Gatuz Gitanjali Subramanya Hyun-Young Jeong Susan L. Uprichard Michael E. Johnson 《PloS one》2013,8(10)
Development of drug-resistant mutations has been a major problem with all currently developed Hepatitis C Virus (HCV) NS3/4A inhibitors, including the two FDA approved drugs, significantly reducing the efficacy of these inhibitors. The high incidence of drug-resistance mutations and the limited utility of these inhibitors against only genotype 1 highlight the need for novel, broad-spectrum HCV therapies. Here we used high-throughput screening (HTS) to identify low molecular weight inhibitors against NS3/4A from multiple genotypes. A total of 40,967 compounds from four structurally diverse molecular libraries were screened by HTS using fluorescence-based enzymatic assays, followed by an orthogonal binding analysis using surface plasmon resonance (SPR) to eliminate false positives. A novel small molecule compound was identified with an IC50 value of 2.2 µM against the NS3/4A from genotype 1b. Mode of inhibition analysis subsequently confirmed this compound to be a competitive inhibitor with respect to the substrate, indicating direct binding to the protease active site, rather than to the allosteric binding pocket that was discovered to be the binding site of a few recently discovered small molecule inhibitors. This newly discovered inhibitor also showed promising inhibitory activity against the NS3/4As from three other HCV genotypes, as well as five common drug-resistant mutants of genotype 1b NS3/4A. The inhibitor was selective for NS3 from multiple HCV genotypes over two human serine proteases, and a whole cell lysate assay confirmed inhibitory activity in the cellular environment. This compound provides a lead for further development of potentially broader spectrum inhibitors. 相似文献
19.
Peters CS Liang X Li S Kannan S Peng Y Taub R Diamond RH 《The Journal of biological chemistry》2001,276(17):13718-13726
20.
Role of PRL-3, a human muscle-specific tyrosine phosphatase, in angiotensin-II signaling 总被引:13,自引:0,他引:13
Matter WF Estridge T Zhang C Belagaje R Stancato L Dixon J Johnson B Bloem L Pickard T Donaghue M Acton S Jeyaseelan R Kadambi V Vlahos CJ 《Biochemical and biophysical research communications》2001,283(5):1061-1068
Action of protein kinases and phosphatases contributes to myocardial hypertrophy. PRL-3, a protein tyrosine phosphatase, was identified in a cDNA library from an explanted human heart obtained from a patient with idiopathic cardiomyopathy. PRL-3 is expressed in heart and skeletal muscle, exhibiting approximately 76% identity to the ubiquitous tyrosine phosphatase PRL-1, which was reported to increase cell proliferation. PRL-3 was cloned into E. coli and purified using affinity chromatography. PRL-3 activity was determined using the substrate 6,8-difluoro-4-methylumbelliferyl phosphate, and was inhibited by vanadate and analogs. HEK293 cells expressing PRL-3 demonstrated increased growth rates versus nontransfected cells or cells transfected with the catalytically inactive C104S PRL-3 mutant. The tyrosine phosphatase inhibitor, potassium bisperoxo (bipyridine) oxovanadate V, normalizes the growth rate of PRL-3 expressing cells to that of parental HEK293 cells in a concentration-dependent manner. Using FLIPR analysis, parental HEK293 cells mobilize calcium when stimulated with angiotensin-II (AngII). However, calcium mobilization is inhibited in cells expressing wild-type PRL-3 when stimulated with AngII, while cells expressing the inactive mutant of PRL-3 mobilize calcium to the same extent as parental HEK293 cells. Western blots comparing PRL-3 transfected cells to parental HEK293 cells showed dephosphorylation of p130(cas) in response to AngII. These data suggest a role for PRL-3 in the modulation of intracellular calcium transients induced by AngII. 相似文献