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Sanders M.P.A.,Radboud University Nijmegen | Sanders M.P.A.,Netherlands cience Center | Roumen L.,VU University Amsterdam | Van Der Horst E.,Leiden University | And 23 more authors.
Journal of Medicinal Chemistry | Year: 2012

We present the systematic prospective evaluation of a protein-based and a ligand-based virtual screening platform against a set of three G-protein-coupled receptors (GPCRs): the β-2 adrenoreceptor (ADRB2), the adenosine A 2A receptor (AA2AR), and the sphingosine 1-phosphate receptor (S1PR1). Novel bioactive compounds were identified using a consensus scoring procedure combining ligand-based (frequent substructure ranking) and structure-based (Snooker) tools, and all 900 selected compounds were screened against all three receptors. A striking number of ligands showed affinity/activity for GPCRs other than the intended target, which could be partly attributed to the fuzziness and overlap of protein-based pharmacophore models. Surprisingly, the phosphodiesterase 5 (PDE5) inhibitor sildenafil was found to possess submicromolar affinity for AA2AR. Overall, this is one of the first published prospective chemogenomics studies that demonstrate the identification of novel cross-pharmacology between unrelated protein targets. The lessons learned from this study can be used to guide future virtual ligand design efforts. © 2012 American Chemical Society.

Van Der Stelt M.,Merck And Co. | Van Der Stelt M.,Netherlands Translational Research Center | Cals J.,Merck And Co. | Broeders-Josten S.,Merck And Co. | And 12 more authors.
Journal of Medicinal Chemistry | Year: 2011

Here, we report the identification and optimization of 1-(4-(pyridin-2-yl) benzyl)imidazolidine-2,4-dione derivatives as a novel chemotype with selective cannabinoid CB2 receptor agonist activity. 1 is a potent and selective cannabinoid CB2 receptor agonist (hCB2 pEC 50 = 8.6). The compound was found to be metabolically unstable, which resulted in low oral bioavailability in rat (F po = 4%) and possessed off-target activity at the hERG ion channel (pK i = 5.5). Systematic modification of physicochemical properties, such as lipophilicity and basicity, was used to optimize the pharmacokinetic profile and hERG affinity of this novel class of cannabinoid CB2 receptor agonists. This led to the identification of 44 as a potent, selective, and orally bioavailable cannabinoid CB2 receptor agonist (hCB2 pEC 50 = 8.0; hERG pK i < 4; F po = 100%), which was active in a rat spinal nerve ligation model of neuropathic pain. © 2011 American Chemical Society.

Watts A.O.,VU University Amsterdam | Verkaar F.,VU University Amsterdam | Verkaar F.,Merck And Co. | Van Der Lee M.M.C.,Merck And Co. | And 9 more authors.
Journal of Biological Chemistry | Year: 2013

Background: CCX-CKR is considered to be a chemokine decoy receptor that is unable to signal. Results: Chemokines induce β-arrestin recruitment to CCX-CKR and pertussis toxin (PTX)-dependent CRE activity. Conclusion: PTX-sensitive G proteins hinder CCX-CKR coupling to other G proteins and consequently keep receptors silent. Significance: Recruitment of β-arrestin to CCX-CKR requests re-evaluation of the signaling capacity of this atypical receptor. © 2013 by The American Society for Biochemistry and Molecular Biology, Inc.

van der Lee M.M.C.,Merck And Co. | Verkaar F.,VU University Amsterdam | Wat J.W.Y.,Merck And Co. | van Offenbeek J.,VU University Amsterdam | And 6 more authors.
Cellular Signalling | Year: 2013

Parathyroid hormone (PTH) is an anabolic agent that mediates bone formation through activation of the Gαs-, Gαq- and β-arrestin-coupled parathyroid hormone receptor type 1 (PTH1R). Pharmacological evidence based on the effect of PTH(7-34), a PTH derivative that is said to preferentially activate β-arrestin signaling through PTH1R, suggests that PTH1R-activated β-arrestin signaling mediates anabolic effects on bone. Here, we performed a thorough evaluation of PTH(7-34) signaling behaviour using quantitative assays for β-arrestin recruitment, Gαs- and Gαq-signaling. We found that PTH(7-34) inhibited PTH-induced cAMP accumulation, but was unable to induce β-arrestin recruitment, PTH1R internalization and ERK1/2 phosphorylation in HEK293, CHO and U2OS cells. Thus, the β-arrestin bias of PTH(7-34) is not apparent in every cell type examined, suggesting that correlating in vivo effects of PTH(7-34) to in vitro pharmacology should be done with caution. © 2012 Elsevier Inc.

Maia A.R.R.,Netherlands Cancer Institute | De Man J.,Netherlands Translational Research Center | Boon U.,Netherlands Cancer Institute | Janssen A.,Netherlands Cancer Institute | And 14 more authors.
Annals of Oncology | Year: 2015

Background: Triple-negative breast cancers (TNBC) are considered the most aggressive type of breast cancer, for which no targeted therapy exists at the moment. These tumors are characterized by having a high degree of chromosome instability and often overexpress the spindle assembly checkpoint kinase TTK. To explore the potential of TTK inhibition as a targeted therapy in TNBC, we developed a highly potent and selective small molecule inhibitor of TTK, NTRC 0066-0. Results and Conclusions: The compound is characterized by long residence time on the target and inhibits the proliferation of a wide variety of human cancer cell lines with potency in the same range as marketed cytotoxic agents. In cell lines and in mice, NTRC 0066-0 inhibits the phosphorylation of a TTK substrate and induces chromosome missegregation. NTRC 0066-0 inhibits tumor growth in MDA-MB-231 xenografts as a single agent after oral application. To address the effect of the inhibitor in breast cancer, we used a well-defined mouse model that spontaneously develops breast tumors that share key morphologic and molecular features with human TNBC. Our studies show that combination of NTRC 0066-0 with a therapeutic dose of docetaxel resulted in doubling of mouse survival and extended tumor remission, without toxicity. Furthermore, we observed that treatment efficacy is only achieved upon co-administration of the two compounds, which suggests a synergistic in vivo effect. Therefore, we propose TTK inhibition as a novel therapeutic target for neoadjuvant therapy in TNBC. © The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

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