Evaluation of a series of bicyclic CXCR2 antagonists

Walters, Iain A. S.; Austin, Caroline A.; Austin, Rupert P.; Bonnert, Roger V.; Cage, Peter; Christie, Mark; Ebden, Mark R.; Gardiner, Stuart D.; Grahames, Caroline; Hill, Steven M.; Hunt, Fraser; Jewell, R. A.; Lewis, Shirley; Martin, Iain; Nicholls, David J.; Robinson, David M.

doi:10.1016/j.bmcl.2007.11.039

Cited by 59 publications

(40 citation statements)

References 23 publications

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“…Antagonism and affinity differences were evaluated by comparing the ability of compounds to inhibit both CXCL8-mediated calcium responses and the binding of radio-labeled CXCL8 to membranes from HEK293 cells expressing recombinant receptors. Consistent with findings from previous studies (Podolin et al, 2002;Walters et al, 2008), both compounds A and B were at least 100 times more potent antagonists of CXCR2 compared with CXCR1 (Table 1). Moreover, compound A is representative of a diverse chemical series that shows a consistent 100-fold decrease in apparent affinity against CXCR1 compared with CXCR2 (data not shown).…”

Section: Resultssupporting

confidence: 90%

Identification of a Putative Intracellular Allosteric Antagonist Binding-Site in the CXC Chemokine Receptors 1 and 2

Nicholls

Tomkinson²,

Wiley³

et al. 2008

Mol Pharmacol

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The chemokine receptors CXCR1 and CXCR2 are G-proteincoupled receptors (GPCRs) implicated in mediating cellular functions associated with the inflammatory response. Potent CXCR2 receptor antagonists have been discovered, some of which have recently entered clinical development. The aim of this study was to identify key amino acid residue differences between CXCR1 and CXCR2 that influence the relative antagonism by two compounds that have markedly different chemical structures. By investigating the effects of domain switching and point mutations, we found that the second extracellular loop, which contained significant amino acid sequence diversity, was not important for compound antagonism. We were surprised to find that switching the intracellular C-terminal 60 amino acid domains of CXCR1 and CXCR2 caused an apparent reversal of antagonism at these two receptors. Further investigation showed that a single amino acid residue, lysine 320 in CXCR2 and asparagine 311 in CXCR1, plays a predominant role in describing the relative antagonism of the two compounds. Homology modeling studies based on the structure of bovine rhodopsin indicated a potential intracellular antagonist binding pocket involving lysine 320. We conclude that residue 320 in CXCR2 forms part of a potential allosteric binding pocket on the intracellular side of the receptor, a site that is distal to the orthosteric site commonly assumed to be the location of antagonist binding to GPCRs. The existence of a common intracellular allosteric binding site at GPCRs related to CXCR2 may be of value in the design of novel antagonists for therapeutic intervention.Chemokines are small, secreted proteins of 8 to 14 kDa that regulate a broad spectrum of cellular functions and typically induce cell movement along a concentration gradient. There are three groups of chemokines exhibiting characteristic cysteine sequence motifs: the C-X-C, C-C, and C-X3-C families (Horuk, 2001). The emergent role of chemokines in immune and inflammatory responses has identified chemokine receptors as attractive targets for therapeutic intervention in various diseases and disorders (D'Ambrosio et al., 2003). The two GPCRs CXCR1 and CXCR2 have been identified as important mediators of inflammation and display distinct ligand specificities. CXCL8 (interleukin-8) and CXCL6 (granulocyte chemotactic protein-2) interact with both CXCR1 and CXCR2; however, the chemokines CXCL5 (epithelial cell-derived neutrophil-activating protein 78), CXCL7 (neutrophil-activating peptide 2), and CXCL1 (growth-related oncogene-␣) are efficacious for CXCR2 only (Wolf et al., 1998). CXCR2 is expressed on a variety of cells including neutrophils, keratinocytes, mast cells, eosinophils, macrophages, and endothelial and epithelial cells. In addition to chemotaxis, activation of CXCR2 is known to stimulate a variety of cellular responses including calcium mobilization, adhesion molecule up-regulation, and angiogenesis. These pleiotropic effects have implicated CXCR2 in the pathology of various diseases wit...

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Section: Resultssupporting

confidence: 90%

Identification of a Putative Intracellular Allosteric Antagonist Binding-Site in the CXC Chemokine Receptors 1 and 2

Nicholls

Tomkinson²,

Wiley³

et al. 2008

Mol Pharmacol

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“…Whereas natural ligands such as CXCL1/8 bind to the extracellular orthosteric binding site at the N terminus and extracellular loops of CXCR1/2 (Allen et al, 2007), small-molecule antagonists seem to bind to allosteric sites at the seven-transmembrane domain, as demonstrated for repertaxin at CXCR1 (Bertini et al, 2004;Allegretti et al, 2005), or to a putative intracellular site of the CXCR2 receptor, as shown for the diarylurea SB332235 (Nicholls et al, 2008). Studies using radiolabeled SB265610 demonstrated competition between this member of the diarylurea class of antagonists and the structurally unrelated thiazolopyrimidine class (Walters et al, 2008), suggesting that both classes share a common binding site (de Kruijf et al, 2009). Conversely, radiolabeled SB265610 failed to compete with structurally unrelated imidazolylpyrimidine antagonists (Ho et al, 2006;de Kruijf et al, 2009), supporting the notion that distinct allosteric antagonist sites exist on CXCR2 (Ho et al, 2006;de Kruijf et al, 2009).…”

Section: Discussionmentioning

confidence: 93%

Nicotinamide Glycolates Antagonize CXCR2 Activity through an Intracellular Mechanism

Maeda¹,

Quinn²,

Schepetkin³

et al. 2009

J Pharmacol Exp Ther

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The chemokine receptors CXCR1/2 are involved in a variety of inflammatory diseases, including chronic obstructive pulmonary disease. Several classes of allosteric small-molecule CXCR1/2 antagonists have been developed. The data presented here describe the cellular pharmacology of the acid and ester forms of the nicotinamide glycolate pharmacophore, a potent antagonist of CXCR2 signaling by the chemokines CXCL1 and CXCL8. H acid was not internalized by neutrophils but was sufficient alone to inhibit CXCL1-stimulated calcium flux in neutrophils that were permeabilized by electroporation to permit its direct access to the cell interior. Neutrophil efflux of the acid was probenecid-sensitive, consistent with an organic acid transporter. These data support a mechanism wherein the nicotinamide glycolate ester serves as a lipophilic precursor that efficiently translocates into the intracellular neutrophil space to liberate the active acid form of the pharmacophore, which then acts at an intracellular site. Rapid inactivation by plasma esterases precluded use in vivo, but the mechanism elucidated provided insight for new nicotinamide pharmacophore classes with therapeutic potential.Chemoattractant cytokines, or chemokines, promote the directed migration of polymorphonuclear leukocytes (PMNs) to sites of inflammation in a process known as chemotaxis. Among the most important chemokines released during inflammatory responses are the "Cys-XaaCys" (CXC) or ␣ chemokines, which are characterized by the presence of an intervening amino acid between con-

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“…We also examined the receptor selectivity underpinning the CXCL8-induced activation of NF-B and the CXCL8-induced potentiation of Bcl-2 expression. Blockade of CXCR2 receptor signaling was effected using a small-molecule CXCR2 receptor antagonist, AZ10397767, which when administered at a concentration (20 nM) selectively antagonizes CXCR2 activation but has no activity on the CXCR1 receptor in vitro (Walters et al, 2008). In EMSA analysis, CXCL8-promoted DNA binding of NF-B was attenuated in the presence of AZ10397767 (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Oxaliplatin (L-OHP) (Woynarowski et al, 2000) was obtained from the Bridgewater Chemotherapy Suite, Belfast City Hospital. AZ10397767 (AZ767) was kindly provided by Dr. Simon T. Barry and Dr. David Blakey (AstraZeneca, Alderley Park, Cheshire, UK) (Walters et al, 2008).…”

Section: Methodsmentioning

confidence: 99%

Chemotherapy-Induced CXC-Chemokine/CXC-Chemokine Receptor Signaling in Metastatic Prostate Cancer Cells Confers Resistance to Oxaliplatin through Potentiation of Nuclear Factor-κB Transcription and Evasion of Apoptosis

Wilson

Purcell²,

Seaton³

et al. 2008

J Pharmacol Exp Ther

104

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Constitutive activation of nuclear factor (NF)-B is linked with the intrinsic resistance of androgen-independent prostate cancer (AIPC) to cytotoxic chemotherapy. Interleukin-8 (CXCL8) is a transcriptional target of NF-B whose expression is elevated in AIPC. This study sought to determine the significance of CXCL8 signaling in regulating the response of AIPC cells to oxaliplatin, a drug whose activity is reportedly sensitive to NF-B activity. Administration of oxaliplatin to PC3 and DU145 cells increased NF-B activity, promoting antiapoptotic gene transcription. In addition, oxaliplatin increased the transcription and secretion of CXCL8 and the related CXC-chemokine CXCL1 and increased the transcription and expression of CXC-chemokine receptors, especially CXC-chemokine receptor (CXCR) 2, which transduces the biological effects of CXCL8 and CXCL1.

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Evaluation of a series of bicyclic CXCR2 antagonists

Cited by 59 publications

References 23 publications

Identification of a Putative Intracellular Allosteric Antagonist Binding-Site in the CXC Chemokine Receptors 1 and 2

Identification of a Putative Intracellular Allosteric Antagonist Binding-Site in the CXC Chemokine Receptors 1 and 2

Nicotinamide Glycolates Antagonize CXCR2 Activity through an Intracellular Mechanism

Chemotherapy-Induced CXC-Chemokine/CXC-Chemokine Receptor Signaling in Metastatic Prostate Cancer Cells Confers Resistance to Oxaliplatin through Potentiation of Nuclear Factor-κB Transcription and Evasion of Apoptosis

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