All Outputs (77)

Modulators of CXCR4 and CXCR7/ACKR3 Function (2019)
Journal Article
Adlere, I., Caspar, B., Arimont, M., Dekkers, S., Visser, K., Stuijt, J., …Leurs, R. (2019). Modulators of CXCR4 and CXCR7/ACKR3 Function. Molecular Pharmacology, 96(6), 737-752. https://doi.org/10.1124/mol.119.117663

Copyright © 2019 by The Author(s). The two G protein-coupled receptors (GPCRs) C-X-C chemokine receptor type 4 (CXCR4) and atypical chemokine receptor 3 (ACKR3) are part of the class A chemokine GPCR family and represent important drug targets for hu... Read More about Modulators of CXCR4 and CXCR7/ACKR3 Function.

Comparison of the ligand‐binding properties of fluorescent VEGF‐A isoforms to VEGF receptor 2 in living cells and membrane preparations using NanoBRET (2019)
Journal Article
Peach, C. J., Kilpatrick, L. E., Woolard, J., & Hill, S. J. (2019). Comparison of the ligand‐binding properties of fluorescent VEGF‐A isoforms to VEGF receptor 2 in living cells and membrane preparations using NanoBRET. British Journal of Pharmacology, 176(17), 3220-3235. https://doi.org/10.1111/bph.14755

Background and Purpose: Vascular Endothelial Growth Factor A (VEGF-A) is a key mediator of angiogenesis. A striking feature of the binding of a fluorescent analogue of VEGF165a to NanoLuciferase-tagged VEGF Receptor 2 (VEGFR2) in living cells is that... Read More about Comparison of the ligand‐binding properties of fluorescent VEGF‐A isoforms to VEGF receptor 2 in living cells and membrane preparations using NanoBRET.

Probe dependency in the determination of ligand binding kinetics at a prototypical G protein-coupled receptor (2019)
Journal Article
Bosma, R., Stoddart, L. A., Georgi, V., Bouzo-Lorenzo, M., Bushby, N., Inkoom, L., …Leurs, R. (2019). Probe dependency in the determination of ligand binding kinetics at a prototypical G protein-coupled receptor. Scientific Reports, 9, Article 7906. https://doi.org/10.1038/s41598-019-44025-5

© 2019, The Author(s). Drug-target binding kinetics are suggested to be important parameters for the prediction of in vivo drug-efficacy. For G protein-coupled receptors (GPCRs), the binding kinetics of ligands are typically determined using associat... Read More about Probe dependency in the determination of ligand binding kinetics at a prototypical G protein-coupled receptor.

Complex formation between VEGFR2 and the β2-adrenoceptor (2019)
Journal Article
Kilpatrick, L. E., Alcobia, D. C., White, C. W., Peach, C. J., Glenn, J. R., Zimmerman, K., …Hill, S. J. (2019). Complex formation between VEGFR2 and the β2-adrenoceptor. Cell Chemical Biology, 26(6), 830-841.e9. https://doi.org/10.1016/j.chembiol.2019.02.014

Vascular endothelial growth factor (VEGF) is an important mediator of endothelial cell proliferation and angiogenesis via its receptor VEGFR2. A common tumor associated with elevated VEGFR2 signaling is infantile hemangioma that is caused by a rapid... Read More about Complex formation between VEGFR2 and the β2-adrenoceptor.

A live cell NanoBRET binding assay allows the study of ligand-binding kinetics to the adenosine A3 receptor (2019)
Journal Article
Bouzo-Lorenzo, M., Stoddart, L. A., Xia, L., Jerzman, A. P., Heitman, L. H., Briddon, S. J., & Hill, S. J. (2019). A live cell NanoBRET binding assay allows the study of ligand-binding kinetics to the adenosine A3 receptor. Purinergic Signalling, 15(2), 139–153. https://doi.org/10.1007/s11302-019-09650-9

There is a growing interest in understanding the binding kinetics of compounds that bind to G proteincoupled receptors prior to progressing a lead compound into clinical trials. The widely expressed adenosine A3 receptor (A3AR) has been implicated in... Read More about A live cell NanoBRET binding assay allows the study of ligand-binding kinetics to the adenosine A3 receptor.

Probe dependence of allosteric enhancers on the binding affinity of adenosine A1‐receptor agonists at rat and human A1‐receptors measured using NanoBRET (2019)
Journal Article
Cooper, S. L., Soave, M., Jörg, M., Scammells, P. J., Woolard, J., & Hill, S. J. (2019). Probe dependence of allosteric enhancers on the binding affinity of adenosine A1‐receptor agonists at rat and human A1‐receptors measured using NanoBRET. British Journal of Pharmacology, 176(7), 864-878. https://doi.org/10.1111/bph.14575

Background and Purpose: Adenosine is a local mediator that regulates a number of physiological and pathological processes via activation of adenosine A1‐receptors. The activity of adenosine can be regulated at the level of its target receptor via dru... Read More about Probe dependence of allosteric enhancers on the binding affinity of adenosine A1‐receptor agonists at rat and human A1‐receptors measured using NanoBRET.

Binding kinetics of ligands acting at GPCRs (2019)
Journal Article
Sykes, D. A., Stoddart, L. A., Kilpatrick, L. E., & Hill, S. J. (2019). Binding kinetics of ligands acting at GPCRs. Molecular and Cellular Endocrinology, 485, 9-19. https://doi.org/10.1016/j.mce.2019.01.018

The influence of drug-receptor binding kinetics has often been overlooked during the development of new therapeutics that target G protein-coupled receptors (GPCRs). Over the last decade there has been a growing understanding that an in-depth knowled... Read More about Binding kinetics of ligands acting at GPCRs.

Structure-based exploration and pharmacological evaluation of N-substituted piperidin-4-yl-methanamine CXCR4 chemokine receptor antagonists (2018)
Journal Article
Adlere, I., Sun, S., Zarca, A., Roumen, L., Gozelle, M., Viciano, C. P., …Leurs, R. (2019). Structure-based exploration and pharmacological evaluation of N-substituted piperidin-4-yl-methanamine CXCR4 chemokine receptor antagonists. European Journal of Medicinal Chemistry, 162, 631-649. https://doi.org/10.1016/j.ejmech.2018.10.060

Using the available structural information of the chemokine receptor CXCR4, we present hit finding and hit exploration studies that make use of virtual fragment screening, design, synthesis and structure-activity relationship (SAR) studies. Fragment... Read More about Structure-based exploration and pharmacological evaluation of N-substituted piperidin-4-yl-methanamine CXCR4 chemokine receptor antagonists.

Visualising ligand-binding to a GPCR in vivo using nanoBRET (2018)
Journal Article
Carvalheira Alcobia, D., Ziegler, A. I., Kondrashov, A., Comeo, E., Mistry, S., Kellam, B., …Sloan, E. K. (2018). Visualising ligand-binding to a GPCR in vivo using nanoBRET. iScience, 6(8), 280-288. https://doi.org/10.1016/j.isci.2018.08.006

© 2018 The Author(s) The therapeutic action of a drug depends on its ability to engage with its molecular target in vivo. However, current drug discovery strategies quantify drug levels within organs rather than determining the binding of drugs direc... Read More about Visualising ligand-binding to a GPCR in vivo using nanoBRET.

Real-Time Ligand Binding of Fluorescent VEGF-A Isoforms that Discriminate between VEGFR2 and NRP1 in Living Cells (2018)
Journal Article
Peach, C. J., Kilpatrick, L. E., Friedman-Ohana, R., Zimmerman, K., Robers, M. B., Wood, K. V., …Hill, S. J. (2018). Real-Time Ligand Binding of Fluorescent VEGF-A Isoforms that Discriminate between VEGFR2 and NRP1 in Living Cells. Cell Chemical Biology, 25(10), 1208-1218.e5. https://doi.org/10.1016/j.chembiol.2018.06.012

© 2018 The Author(s) Fluorescent VEGF-A isoforms have been evaluated for their ability to discriminate between VEGFR2 and NRP1 in real-time ligand binding studies in live cells using BRET. To enable this, we synthesized single-site (N-terminal cystei... Read More about Real-Time Ligand Binding of Fluorescent VEGF-A Isoforms that Discriminate between VEGFR2 and NRP1 in Living Cells.

Molecular pharmacology of VEGF-A isoforms: binding and signalling at VEGFR2 (2018)
Journal Article
Peach, C., Mignone, V., Arruda, M., Alcobia, D., Hill, S., Kilpatrick, L., & Woolard, J. (2018). Molecular pharmacology of VEGF-A isoforms: binding and signalling at VEGFR2. International Journal of Molecular Sciences, 19(4), Article 1264. https://doi.org/10.3390/ijms19041264

Vascular endothelial growth factor-A (VEGF-A) is a key mediator of angiogenesis, signalling via the class IV tyrosine kinase receptor family of VEGF Receptors (VEGFRs). Although VEGF-A ligands bind to both VEGFR1 and VEGFR2, they primarily signal via... Read More about Molecular pharmacology of VEGF-A isoforms: binding and signalling at VEGFR2.

Synthesis and evaluation of the first fluorescent antagonists of the human P2Y2 receptor based on AR-C118925 (2018)
Journal Article
Conroy, S., Kindon, N., Glenn, J., Stoddart, L. A., Lewis, R. J., Hill, S. J., …Stocks, M. J. (2018). Synthesis and evaluation of the first fluorescent antagonists of the human P2Y2 receptor based on AR-C118925. Journal of Medicinal Chemistry, 61(7), https://doi.org/10.1021/acs.jmedchem.8b00139

The human P2Y2 receptor (hP2Y2R) is a G protein-coupled receptor that shows promise as a therapeutic target for many important conditions including anti-metastatic cancer therapy and more recently for the treatment of idiopathic pulmonary fibrosis. A... Read More about Synthesis and evaluation of the first fluorescent antagonists of the human P2Y2 receptor based on AR-C118925.

Development of novel fluorescent histamine H?-receptor antagonists to study ligand-binding kinetics in living cells (2018)
Journal Article
Stoddart, L. A., Vernall, A. J., Bouzo-Lorenzo, M., Bosma, R., Kooistra, A. J., de Graaf, C., …Hill, S. J. (2018). Development of novel fluorescent histamine H₁-receptor antagonists to study ligand-binding kinetics in living cells. Scientific Reports, 8, Article 1572. https://doi.org/10.1038/s41598-018-19714-2

The histamine H1-receptor (H1R) is an important mediator of allergy and inflammation. H1R antagonists have particular clinical utility in allergic rhinitis and urticaria. Here we have developed six novel fluorescent probes for this receptor that are... Read More about Development of novel fluorescent histamine H?-receptor antagonists to study ligand-binding kinetics in living cells.

A non-imaging high throughput approach to chemical library screening at the unmodified adenosine-A3 receptor in living cells (2017)
Journal Article
Arruda, M. A., Stoddart, L. A., Gherbi, K., Briddon, S. J., Kellam, B., & Hill, S. J. (in press). A non-imaging high throughput approach to chemical library screening at the unmodified adenosine-A3 receptor in living cells. Frontiers in Pharmacology, 8(908), https://doi.org/10.3389/fphar.2017.00908

Recent advances in fluorescent ligand technology have enabled the study of G protein-coupled receptors in their native environment without the need for genetic modification such as addition of N-terminal fluorescent or bioluminescent tags. Here, we h... Read More about A non-imaging high throughput approach to chemical library screening at the unmodified adenosine-A3 receptor in living cells.

A monoclonal antibody raised against a thermo-stabilised ?1-adrenoceptor interacts with extracellular loop 2 and acts as a negative allosteric modulator of a sub-set of 1- adrenoceptors expressed in stable cell lines (2017)
Journal Article
Soave, M., Cseke, G., Hutchings, C. J., Brown, A. J., Woolard, J., & Hill, S. J. (2018). A monoclonal antibody raised against a thermo-stabilised ?1-adrenoceptor interacts with extracellular loop 2 and acts as a negative allosteric modulator of a sub-set of 1- adrenoceptors expressed in stable cell lines. Biochemical Pharmacology, 147, https://doi.org/10.1016/j.bcp.2017.10.015

Recent interest has focused on antibodies that can discriminate between different receptor conformations. Here we have characterised the effect of a monoclonal antibody (mAb3), raised against a purified thermo-stabilised turkey ?1-adrenoceptor (?1AR-... Read More about A monoclonal antibody raised against a thermo-stabilised ?1-adrenoceptor interacts with extracellular loop 2 and acts as a negative allosteric modulator of a sub-set of 1- adrenoceptors expressed in stable cell lines.

Characterisation of endogenous A2A and A2B receptor-mediated cyclic AMP responses in HEK 293 cells using the GloSensor™ biosensor: evidence for an allosteric mechanism of action for the A2B-selective antagonist PSB 603 (2017)
Journal Article
Goulding, J., May, L. T., & Hill, S. J. (2018). Characterisation of endogenous A2A and A2B receptor-mediated cyclic AMP responses in HEK 293 cells using the GloSensor™ biosensor: evidence for an allosteric mechanism of action for the A2B-selective antagonist PSB 603. Biochemical Pharmacology, 147, https://doi.org/10.1016/j.bcp.2017.10.013

Endogenous adenosine A2B receptors (A2BAR) mediate cAMP accumulation in HEK 293 cells. Here we have used a biosensor to investigate the mechanism of action of the A2BAR antagonist PSB 603 in HEK 293 cells. The A2A agonist CGS 21680 elicited a small r... Read More about Characterisation of endogenous A2A and A2B receptor-mediated cyclic AMP responses in HEK 293 cells using the GloSensor™ biosensor: evidence for an allosteric mechanism of action for the A2B-selective antagonist PSB 603.

Novel selective ?1-adrenoceptor antagonists for concomitant cardiovascular and respiratory disease (2017)
Journal Article
Baker, J. G., Gardiner, S. M., Woolard, J., Fromont, C., Jadhav, G. P., Mistry, S. N., …Fischer, P. M. (2017). Novel selective β1-adrenoceptor antagonists for concomitant cardiovascular and respiratory disease. FASEB Journal, 31(7), 3150-3166. https://doi.org/10.1096/fj.201601305R

?-Blockers reduce mortality and improve symptoms in people with heart disease. However, current clinically available ?-blockers have poor selectivity for the cardiac ?1-adrenoceptor (AR) over the lung ?2-AR. Unwanted ?2-blockade risks causing life-th... Read More about Novel selective ?1-adrenoceptor antagonists for concomitant cardiovascular and respiratory disease.

Real-time analysis of the binding of fluorescent VEGF165a to VEGFR2 in living cells: Effect of receptor tyrosine kinase inhibitors and fate of internalized agonist-receptor complexes (2017)
Journal Article
Kilpatrick, L. E., Friedman-Ohana, R., Alcobia, D. C., Riching, K., Peach, C. J., Wheal, A. J., …Hill, S. J. (2017). Real-time analysis of the binding of fluorescent VEGF165a to VEGFR2 in living cells: Effect of receptor tyrosine kinase inhibitors and fate of internalized agonist-receptor complexes. Biochemical Pharmacology, 136, 62-75. https://doi.org/10.1016/j.bcp.2017.04.006

© 2017 The Authors Vascular endothelial growth factor (VEGF) is an important mediator of angiogenesis. Here we have used a novel stoichiometric protein-labeling method to generate a fluorescent variant of VEGF (VEGF165a-TMR) labeled on a single cyste... Read More about Real-time analysis of the binding of fluorescent VEGF165a to VEGFR2 in living cells: Effect of receptor tyrosine kinase inhibitors and fate of internalized agonist-receptor complexes.

Design and elaboration of a tractable tricyclic scaffold to synthesize druglike inhibitors of dipeptidyl peptidase-4 (DPP-4), antagonists of the C–C Chemokine Receptor Type 5 (CCR5), and highly potent and selective phosphoinositol-3 Kinase δ (PI3Kδ) inhibitors (2017)
Journal Article
Schwehm, C., Kellam, B., Garces, A., Hill, S. J., Kindon, N., Bradshaw, T. D., …Stocks, M. (2017). Design and elaboration of a tractable tricyclic scaffold to synthesize druglike inhibitors of dipeptidyl peptidase-4 (DPP-4), antagonists of the C–C Chemokine Receptor Type 5 (CCR5), and highly potent and selective phosphoinositol-3 Kinase δ (PI3Kδ) inhibitors. Journal of Medicinal Chemistry, 60(4), https://doi.org/10.1021/acs.jmedchem.6b01801

A novel molecular scaffold has been synthesized, and its incorporation into new analogues of biologically active molecules across multiple target classes will be discussed. In these studies, we have shown use of the tricyclic scaffold to synthesize p... Read More about Design and elaboration of a tractable tricyclic scaffold to synthesize druglike inhibitors of dipeptidyl peptidase-4 (DPP-4), antagonists of the C–C Chemokine Receptor Type 5 (CCR5), and highly potent and selective phosphoinositol-3 Kinase δ (PI3Kδ) inhibitors.

Structure-activity relationships of the sustained effects of adenosine A2A receptor agonists driven by slow dissociation kinetics (2017)
Journal Article
Hothersall, J. D., Guo, D., Sarda, S., Sheppard, R. J., Chen, H., Keur, W., …Rawlins, P. B. (2017). Structure-activity relationships of the sustained effects of adenosine A2A receptor agonists driven by slow dissociation kinetics. Molecular Pharmacology, 91(1), https://doi.org/10.1124/mol.116.105551

The duration of action of adenosine A2A receptor (A2A) agonists is critical for their clinical efficacy, and we sought to better understand how this can be optimized. The in vitro temporal response profiles of a panel of A2A agonists were studied usi... Read More about Structure-activity relationships of the sustained effects of adenosine A2A receptor agonists driven by slow dissociation kinetics.