Imidazolylpyrimidine based CXCR2 chemokine receptor antagonists

Ho, Koc-Kan; Auld, Douglas S.; Bohnstedt, Adolph C.; Conti, Paolo; Dokter, Wim H.A.; Erickson, Shawn D.; Feng, Donghai; Inglese, Jim; Kingsbury, Celia; Kultgen, Steven G.; Liu, Rongqiang; Masterson, Christopher M.; Ohlmeyer, Michael; Rong, Yajing; Rooseboom, Martijn; Roughton, Andrew L.; Samama, Philippe; Smit, Martin-Jan; Son, Ellen; Louw, Jaap van der; Vogel, G; Webb, Maria L.; Wijkmans, J. C. H. M.; You, Ming

doi:10.1016/j.bmcl.2006.02.028

Cited by 24 publications

(25 citation statements)

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“…7B). The interactions of compound 1 in both models are in line with the structureactivity relationship investigation described by Ho et al (2006), which emphasizes the importance of the long hydrophobic octane moiety as well as the geometry and directionality of the imidazole acceptor group. To assess the involvement of these five residues, we constructed the mutants F130 Table 5) the affinity of compound 1 is slightly decreased at Q216 5.43 E (pK i ϭ 6.5) and significantly decreased for F220 5.47 L (pK i ϭ 6.1) and L271 6.55 A (pK i ϭ 6.2).…”

Section: Downloaded Fromsupporting

confidence: 77%

“…In view of their therapeutic potential, the search for CXCR2 antagonists has been extensive and has led to the identification of different classes of CXCR2 antagonist (Li et al, 2003;Widdowson et al, 2004;Baxter et al, 2006;Ho et al, 2006). In our previous publication (de Kruijf et al, 2009), we reported that CXCR2 antagonists of the diarylurea (such as SB265610; see Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Linear 25-kDa polyethylenimine (PEI) was obtained from Polysciences (Warrington, PA), whereas branched 750-kDa PEI was purchased from Sigma (St. Louis, MO). Bovine serum albumin fraction V (BSA) was obtained from Roche (Mannheim, Germany (Bizzarri et al, 2006)] and (S)-2-(2-(1H-imidazol-1-yl)-6-(octylthio)pyrimidin-4-ylamino)-N-(3-ethoxypropyl)-4-methylpentanamide [compound 1 (Erickson et al, 2004;Ho et al, 2006)] were synthesized at Merck Research Laboratories (MSD, Oss, The Netherlands). Oligonucleotide primers for polymerase chain reaction (PCR) were synthesized by Biolegio (Nijmegen, The Netherlands).…”

Section: Methodsmentioning

confidence: 99%

“…These studies indicate that CXCR2 is an interesting drug target. In view of this therapeutic potential, different CXCR2 antagonists are being developed (see, for example, Li et al, 2003;Widdowson et al, 2004;Baxter et al, 2006;Ho et al, 2006). Among them, 2-hydroxy-N,Ndimethyl-3-{2-[[(R)-1-(5-methyl-furan-2-yl)-propyl]amino]-3,4-dioxo-cyclobut-1-enylamino}-benzamide (SCH-527123) and repertaxin are currently in phase II clinical trial (http://www.clinicaltrials.gov/ct2/show/NCT01006616; http://www.clinicaltrials.gov/ct2/show/NCT00224406).…”

Section: Introductionmentioning

confidence: 99%

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Identification of a Novel Allosteric Binding Site in the CXCR2 Chemokine Receptor

Kruijf¹,

Lim

Roumen

et al. 2011

Mol Pharmacol

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We have shown previously that different chemical classes of small-molecule antagonists of the human chemokine CXCR2 receptor interact with distinct binding sites of the receptor. Although an intracellular binding site for diarylurea CXCR2 antagonists, such as N-(2-bromophenyl)-NЈ-(7-cyano-1H-benzotriazol-4-yl)urea (SB265610), and thiazolopyrimidine compounds was recently mapped by mutagenesis studies, we now report on an imidazolylpyrimidine antagonist binding pocket in the transmembrane domain of CXCR2. Using different CXCR2 orthologs, chimeric proteins, site-directed mutagenesis, and in silico modeling, we have elucidated the binding mode of this antagonist. Our in silico-guided mutagenesis studies indicate that the ligand binding cavity for imidazolylpyrimidine compounds in CXCR2 is located between transmembrane (TM) helices 3 (Phe130 3.36 ), 5 (Ser217 5.44 , Phe220 5.47 ), and 6 (Asn268 6.52 , Leu271 6.55 ) and suggest that these antagonists enter CXCR2 via the TM5-TM6 interface. It is noteworthy that the same interface is postulated as the ligand entry channel in the opsin receptor and is occupied by lipid molecules in the recently solved crystal structure of the CXCR4 chemokine receptor, suggesting a general ligand entrance mechanism for nonpolar ligands to G protein-coupled receptors. The identification of a novel allosteric binding cavity in the TM domain of CXCR2, in addition to the previously identified intracellular binding site, shows the diversity in ligand recognition mechanisms by this receptor and offers new opportunities for the structure-based design of small allosteric modulators of CXCR2 in the future.

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confidence: 77%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Identification of a Novel Allosteric Binding Site in the CXCR2 Chemokine Receptor

Kruijf¹,

Lim

Roumen

et al. 2011

Mol Pharmacol

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“…Well-established is the chemoattraction of neutrophils into inflamed regions after CXCL5-CXCR2 interaction (9). Antagonists to the CXCR2 receptor prevent neutrophil attraction and reduce the inflammatory response (26,27). CXCR2 is also involved in chemokine-induced migration of natural killer and T cells (27,28).…”

Section: Discussionmentioning

confidence: 99%

Disrupted Expression of CXCL5 in Colorectal Cancer Is Associated with Rapid Tumor Formation in Rats and Poor Prognosis in Patients

Speetjens

Kuppen²,

Sandel³

et al. 2008

Clinical Cancer Research

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Purpose: We isolated a subline (CC531M) from the CC531S rat colon carcinoma cell line, which grows and metastasizes much more rapidly than CC531S. We found, using RNA expression profiling, that one of the major changes in the CC531M cell line was a 5.8-fold reduction of the chemokine CXCL5. The purpose of this study was to determine the effect of CXCL5 expression on colorectal tumor growth and metastasis. Experimental Design: CC531 clones were generated with either knockdown or restored expression of CXCL5. These clones were inoculated in the liver of rats. In addition, in two independent cohorts of colorectal cancer patients, the level of CXCL5 expression was determined and associated to clinical variables. Results: Knockdown of CXCL5 expression in CC531S resulted in rapid tumor growth and increased number of metastasis, whereas restored expression of CXCL5 in CC531M resulted in a return of the ''mild'' tumor growth pattern of the parental cell line CC531S. In vitro, no difference was found in proliferation rate between clones with either high or low expression of CXCL5, suggesting that environmental interactions directed by CXCL5 determine tumor outgrowth. Finally, the importance of our findings was established for patients with colorectal cancer. We found that low expression of CXCL5 was significantly associated with poor prognosis for colorectal cancer patients. CXCL5 showed a trend (P = 0.05) for a positive correlation with intratumoral CD8 + T-cell infiltration, suggesting a possible explanation for the observed poorer prognosis. Conclusions: Our results show that CXCL5 is important in growth and development of colorectal cancer, implicating a future role in both cancer therapy and diagnosis.Colorectal cancer is one of the three leading causes of cancerrelated death among men and women in the western world (1, 2). Despite curative surgical resection of the primary tumor, 40% to 50% of the patients ultimately die of metastases (3). Tumor growth and metastasis result from a complex cascade of biological processes. Therefore, knowing key factors in these processes is crucial to design new treatment modalities.In a previous paper, we reported the in vivo selection of an aggressive rat colorectal cell line (CC531M) from the welldescribed CC531S cell line (4, 5). The present study was initiated to identify factors that contribute to rapid growth and metastatic capacity of CC531M. In this study, we focus on the chemokine CXCL5.CXCL5 is a member of the subfamily of lipopolysacharideinducible ELR + CXC chemokines (6). It functions, mainly through interaction with the CXCR2 receptor, both as a chemoattractant and as an angiogenic factor (7 -10). CXCL5 is expressed in the epithelial cells of the colon and overexpressed in colorectal cancer (11,12). It has been reported that CXCL5 plays a role in development and metastasis of several cancer types (13 -15). CXCL5 contributes to the in vivo growth and angiogenic potential of non -small cell lung cancer. Homogenates of human non -small cell lung cancer specimens...

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Low Molecular Weight CXCR2 Antagonists as Promising Therapeutics

Mihara¹,

Wijkmans²

2010

Methods and Principles in Medicinal Chemistry

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The chemokine receptor CXCR2 recognizes endogenous chemokines that possess a N-terminal Glu-Leu-Arg (ELR) þ amino acid sequence immediately adjacent to their CXC motif. CXCR2 and the closely related receptor CXCR1 are expressed on the cellular surface of leukocytes, notably neutrophils, endothelial cells and a range of other cell types throughout the human body. It has been firmly established now that CXCR2 plays a critical role in the development of numerous inflammatory disorders, wound healing and tumor progression [1-5]. As classically defined for chemokine receptors, CXCR2 mediates cell migration but has also been recognized as a key angiogenic factor [6,7]. These multifunctional roles have drawn increased attention to CXCR2 as a potentially successful drug target for therapeutic intervention in a range of diseases. The first half of this chapter summarizes the biological role of CXCR2 and its involvement, particularly in inflammatory disorders, in order to illuminate the potential clinical impact and relevance of CXCR2 blocking strategies. A review of all currently known low molecular weight (LMW) CXCR2 antagonists is addressed in the second half of this chapter. CXCR2 Ligands and Signal TransductionCXCR2, which shows 78% overall amino acid identity with CXCR1, was first cloned in 1991 out of human promyelocytic leukemia HL60 cells [8]. Subsequent research demonstrated that CXCR2 is the cognate receptor for at least seven structurally related (ELR) þ chemokines, which are growth-related protein (Gro)-a, -b and -c (CXCL1-CXCL3), epithelium-derived neutrophil attractant-78 (ENA-78; CXCL5), granulocyte chemotactic protein-2 (GCP-2; CXCL6), neutrophil-activating peptide-2 (NAP-2; CXCL7) and interleukin-8 (IL-8; CXCL8) [9, 10]. In contrast,

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Imidazolylpyrimidine based CXCR2 chemokine receptor antagonists

Cited by 24 publications

References 5 publications

Identification of a Novel Allosteric Binding Site in the CXCR2 Chemokine Receptor

Identification of a Novel Allosteric Binding Site in the CXCR2 Chemokine Receptor

Disrupted Expression of CXCL5 in Colorectal Cancer Is Associated with Rapid Tumor Formation in Rats and Poor Prognosis in Patients

Low Molecular Weight CXCR2 Antagonists as Promising Therapeutics

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