Virtual Screening Targeting the Urokinase Receptor, Biochemical and Cell-Based Studies, Synthesis, Pharmacokinetic Characterization, and Effect on Breast Tumor Metastasis

Wang, Fang; Li, Jing; Sinn, Anthony L.; Knabe, William E.; Khanna, May; Jo, Inha; Silver, Jayne M.; Oh, Kyungsoo; Li, Liwei; Sandusky, George E.; Sledge, George W.; Nakshatri, Harikrishna; Jones, David R.; Pollok, Karen E.; Meroueh, Samy O.

doi:10.1021/jm200782y

Cited by 33 publications

(59 citation statements)

References 37 publications

(90 reference statements)

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“…However, recent experimental evidence indicates that some members of the MMP family behave as tumor-suppressor enzymes and may therefore be regarded as antitargets in cancer therapy (46). Moreover, small-molecule inhibitors of uPA binding to uPAR have been recently described (47,48).…”

Section: Discussionmentioning

confidence: 99%

Discovery of New Small Molecules Targeting the Vitronectin-Binding Site of the Urokinase Receptor That Block Cancer Cell Invasion

Rea

Lavecchia

Giovanni

et al. 2013

Molecular Cancer Therapeutics

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Besides focusing urokinase (uPA) proteolytic activity on the cell membrane, the uPA receptor (uPAR) is able to bind vitronectin, via a direct binding site. Furthermore, uPAR interacts with other cell surface receptors, such as integrins, receptor tyrosine kinases, and chemotaxis receptors, triggering cell-signaling pathways that promote tumor progression. The ability of uPAR to coordinate binding and degradation of extracellular matrix (ECM) and cell signaling makes it an attractive therapeutic target in cancer. We used structure-based virtual screening (SB-VS) to search for small molecules targeting the uPAR-binding site for vitronectin. Forty-one compounds were identified and tested on uPAR-negative HEK-293 epithelial cells transfected with uPAR (uPAR-293 cells), using the parental cell line transfected with the empty vector (V-293 cells) as a control. Compounds 6 and 37 selectively inhibited uPAR-293 cell adhesion to vitronectin and the resulting changes in cell morphology and signal transduction, without exerting any effect on V-293 cells. Compounds 6 and 37 inhibited uPAR-293 cell binding to vitronectin with IC 50 values of 3.6 and 1.2 mmol/L, respectively. Compounds 6 and 37 targeted S88 and R91, key residues for uPAR binding to vitronectin but also for uPAR interaction with the fMLF family of chemotaxis receptors (fMLF-Rs). As a consequence, compounds 6 and 37 impaired uPAR-293 cell migration toward fetal calf serum (FCS), uPA, and fMLF, likely by inhibiting the interaction between uPAR and FPR1, the high affinity fMLF-R. Both compounds blocked in vitro ECM invasion of several cancer cell types, thus representing new promising leads for pharmaceuticals in cancer.

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Section: Discussionmentioning

confidence: 99%

Discovery of New Small Molecules Targeting the Vitronectin-Binding Site of the Urokinase Receptor That Block Cancer Cell Invasion

Rea

Lavecchia

Giovanni

et al. 2013

Molecular Cancer Therapeutics

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“…Insilico screening is one of the most convenient methods to evaluate millions of molecules and obtain novel compounds. In the last few years, In-Silico Virtual Screening (VS) studies were performed by using the docking approach 34,35 . In this work for C. roseus leaves methanolic extract was identified by GC-MS analysis.…”

Section: Introductionmentioning

confidence: 99%

Potential Compound Derived From Catharanthus Roseus to Inhibit Non Small Cell Lung Cancer (Nsclc)

Senthilraja¹,

Kayitare²,

Manivel³

et al. 2015

Int. J. Res. Ayurveda Pharm.

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The aim of this study was to carry out GC-MS analysis of Catharanthus roseus plant leaves extract to inhibit the non-small cell lung cancer. Catharanthus roseus plant leaves were extracted with methanol and five compounds were identified from GC-MS analysis. Epidermal growth factor receptor (EGFR), is a receptor tyrosine kinase (RTK) which is frequently over-expressed and malignant proliferation of non-small cell lung cancer (NSCLC). The 3D crystal structure of the non-small cell lung cancer responsible protein (ID: 2ITO) were retrieved from the protein data bank (PDB). Discovery studio is a well-known suite of software for molecular docking. It is developed and distributed by Accelrys. The protein ligand docking was performed in flexible docking by Discover Studio. From the GC-MS analysis two compounds 4-piperidineacetic,1-acetyl-5-ethyl-2-[3-[2-hydroxyethyl]-1H-indol-2-yl]-a-methyl-methyl ester and 2H-Pyran,tetrahydro-2-[12-penta decynyloxy], exhibited potential effect against human epidermal growth factor receptor (EGFR) responsible for the non-small cell lung cancer.

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“…These processes require a complex interplay of various cell surface-associated proteins (4,5). Among them, the glycosyl-phosphatidylinositol (GPI) anchored urokinase receptor (uPAR) has been implicated in nearly every step of cancer metastasis including adhesion (6-8), migration (8-10), invasion (8,9,11-14), and angiogenesis (9,11,12). This is attributed to its large number of transient and tight protein-protein interactions with soluble and membrane proteins (15).…”

Section: Introductionmentioning

confidence: 99%

“…We have recently reported three classes of compounds that target uPAR (8,13). An anthraquinone-based compound (IPR-803) was shown to bind at submicromolar affinity (0.2 μM) (27) and inhibited the uPAR•uPA interaction with an IC 50 of 10 μM (13).…”

Section: Introductionmentioning

confidence: 99%

Probing Binding and Cellular Activity of Pyrrolidinone and Piperidinone Small Molecules Targeting the Urokinase Receptor

et al. 2013

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The urokinase receptor (uPAR) is a cell-surface protein that is part of an intricate web of transient and tight protein interactions that promote cancer cell invasion and metastasis. Here we evaluate the binding and biological activity of a new class of pyrrolidinone (3) and piperidinone (4) compounds, along with derivatives of previously-identified pyrazole (1) and propylamine (2) compounds. Competition assays revealed that the compounds displaced a fluorescently-labeled peptide (AE147-FAM) with inhibition constant Ki ranging from 6 to 63 μM. Structure-based computational pharmacophore analysis followed by extensive explicit-solvent molecular dynamics simulations and free energy calculations suggested pyrazole-based 1a and piperidinone-based 4 adopt different binding modes, despite their similar two-dimensional structures. In cells, compounds 1b and 1f showed significant inhibition of breast MDA-MB-231 and pancreatic ductal adenocarcinoma (PDAC) cell proliferation, but 4b exhibited no cytotoxicity even at concentrations of 100 μM. 1f impaired MDA-MB-231 invasion, adhesion, and migration in a concentration-dependent manner, while 4b inhibited only invasion. 1f inhibited gelatinase (MMP-9) activity in a concentration-dependent manner, while 4b showed no effect suggesting different mechanisms for inhibition of cell invasion. Signaling studies further highlighted these differences, showing that pyrazole compounds completely inhibited ERK phosphorylation and impaired HIF1α and NF-κB signaling, while pyrrolidinone and piperidinone (3 and 4b) had no effect. Annexin V staining suggested that the effect of pyrazole-based 1f on proliferation was due to cell killing through an apoptotic mechanism.

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Virtual Screening Targeting the Urokinase Receptor, Biochemical and Cell-Based Studies, Synthesis, Pharmacokinetic Characterization, and Effect on Breast Tumor Metastasis

Cited by 33 publications

References 37 publications

Discovery of New Small Molecules Targeting the Vitronectin-Binding Site of the Urokinase Receptor That Block Cancer Cell Invasion

Discovery of New Small Molecules Targeting the Vitronectin-Binding Site of the Urokinase Receptor That Block Cancer Cell Invasion

Potential Compound Derived From Catharanthus Roseus to Inhibit Non Small Cell Lung Cancer (Nsclc)

Probing Binding and Cellular Activity of Pyrrolidinone and Piperidinone Small Molecules Targeting the Urokinase Receptor

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