4 results on '"Pelker J"'
Search Results
2. Studies with neutralizing antibodies suggest CXCL8-mediated neutrophil activation is independent of C-C motif chemokine receptor-like 2 (CCRL2) ligand binding function.
- Author
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Su Z, Brooks J, Pelker J, Andreyeva T, Sobon H, Gifford R, Powers M, Wang J, Dower C, Hegen M, Messing D, Sheehan AD, and Brennan JJ
- Subjects
- Humans, Animals, Mice, Antibodies, Neutralizing pharmacology, Ligands, Signal Transduction, Interleukin-8, Neutrophils metabolism, Receptors, CCR metabolism, Neutrophil Activation
- Abstract
C-C motif chemokine receptor-like 2 (CCRL2) is a non-signaling 7 transmembrane receptor that binds chemotactic ligands to shape leukocyte recruitment to sites of inflammation. However, there is a lack of consensus on the ligands that directly bind CCRL2 or their functional impact. Studies with CCRL2 knockout mice have demonstrated that neutrophils have impaired degranulation and migration in response to CXCL8, where the underlying molecular mechanism is proposed to be due to the formation of CCRL2 heterodimers with the chemokine receptor CXCR2. Herein, we characterized the ligands that bind directly to CCRL2 and interrogated the impact of CCRL2 neutralization on CXCL8 signaling in neutrophils using pharmacological antibody tools. Using flow cytometry and Surface Plasmon Resonance microscopy (SPRm) cell binding experiments, we confirmed that chemerin, but not previously reported C-C chemokines, binds CCRL2. Furthermore, we identified human and mouse CCRL2 antibodies that neutralized chemerin binding to CCRL2. Unexpectedly, we found that neutralization of CCRL2 with these antibodies did not attenuate CXCL8-induced human neutrophil degranulation nor CXCL8-induced murine neutrophil recruitment to the peritoneum. Based on the observed differences in modulating CCRL2 function with neutralizing antibodies compared to the reported CCRL2 deficient murine models, we hypothesize that the ligand binding function of CCRL2 is dispensable for CXCL8 signaling in neutrophils. Finally, extensive profiling of CCRL2 expression on peripheral blood leukocytes revealed monocytes, dendritic cells (DC), and subpopulations of natural killer T (NKT) cells as additional targets, highlighting potential roles for CCRL2 in human cell types beyond neutrophils that warrants future investigation., Competing Interests: All authors were employees of Pfizer during this work. Pfizer provided support in the form of salaries for the following authors: ZS, JB, JP, TA, HS, RG, MP, JW, CD, MH, DM, ADS, JJB). HS is currently an employee of Beam Therapeutics. MP is currently an employee at Sony Biotechnology. The following authors are Pfizer shareholders (JB, JP, TA, RG, JW, MH, DM, ADS, JJB). There are no patents, products in development, nor marketed products associated with this research to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2023 Su et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
- Published
- 2023
- Full Text
- View/download PDF
3. Selective inhibitors of tumor progression loci-2 (Tpl2) kinase with potent inhibition of TNF-alpha production in human whole blood.
- Author
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Wu J, Green N, Hotchandani R, Hu Y, Condon J, Huang A, Kaila N, Li HQ, Guler S, Li W, Tam SY, Wang Q, Pelker J, Marusic S, Hsu S, Perry Hall J, Telliez JB, Cui J, and Lin LL
- Subjects
- Animals, Anti-Inflammatory Agents chemical synthesis, Anti-Inflammatory Agents pharmacokinetics, Female, Humans, Lipopolysaccharides pharmacology, MAP Kinase Kinase Kinases metabolism, Monocytes drug effects, Monocytes immunology, Nitriles chemical synthesis, Nitriles pharmacokinetics, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors pharmacokinetics, Proto-Oncogene Proteins metabolism, Quinolines chemical synthesis, Quinolines pharmacokinetics, Rats, Rats, Sprague-Dawley, Tumor Necrosis Factor-alpha biosynthesis, Anti-Inflammatory Agents chemistry, MAP Kinase Kinase Kinases antagonists & inhibitors, Nitriles chemistry, Protein Kinase Inhibitors chemistry, Proto-Oncogene Proteins antagonists & inhibitors, Quinolines chemistry, Tumor Necrosis Factor-alpha blood
- Abstract
Tpl2 (cot/MAP3K8) is an upstream kinase of MEK in the ERK pathway. It plays an important role in Tumor Necrosis Factor-alpha (TNF-alpha) production and signaling. We have discovered that 8-halo-4-(3-chloro-4-fluoro-phenylamino)-6-[(1H-[1,2,3]triazol-4-ylmethyl)-amino]-quinoline-3-carbonitriles (4) are potent inhibitors of this enzyme. In order to improve the inhibition of TNF-alpha production in LPS-stimulated human blood, a series of analogs with a variety of substitutions around the triazole moiety were studied. We found that a cyclic amine group appended to the triazole ring could considerably enhance potency, aqueous solubility, and cell membrane permeability. Optimization of these cyclic amine groups led to the identification of 8-chloro-4-(3-chloro-4-fluorophenylamino)-6-((1-(1-ethylpiperidin-4-yl)-1H-1,2,3-triazol-4-yl)methylamino)quinoline-3-carbonitrile (34). In a LPS-stimulated rat inflammation model, compound 34 showed good efficacy in inhibiting TNF-alpha production.
- Published
- 2009
- Full Text
- View/download PDF
4. Inhibitors of tumor progression loci-2 (Tpl2) kinase and tumor necrosis factor alpha (TNF-alpha) production: selectivity and in vivo antiinflammatory activity of novel 8-substituted-4-anilino-6-aminoquinoline-3-carbonitriles.
- Author
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Green N, Hu Y, Janz K, Li HQ, Kaila N, Guler S, Thomason J, Joseph-McCarthy D, Tam SY, Hotchandani R, Wu J, Huang A, Wang Q, Leung L, Pelker J, Marusic S, Hsu S, Telliez JB, Hall JP, Cuozzo JW, and Lin LL
- Subjects
- Aminoquinolines pharmacokinetics, Aminoquinolines pharmacology, Animals, Anti-Inflammatory Agents, Non-Steroidal pharmacokinetics, Anti-Inflammatory Agents, Non-Steroidal pharmacology, Crystallography, X-Ray, ErbB Receptors antagonists & inhibitors, ErbB Receptors chemistry, Erlotinib Hydrochloride, Female, Humans, Imidazoles pharmacokinetics, Imidazoles pharmacology, In Vitro Techniques, MAP Kinase Kinase Kinases biosynthesis, MAP Kinase Kinase Kinases chemistry, Microsomes, Liver metabolism, Protein Structure, Tertiary, Proto-Oncogene Proteins biosynthesis, Proto-Oncogene Proteins chemistry, Quinazolines chemistry, Rats, Rats, Sprague-Dawley, Structure-Activity Relationship, Tumor Necrosis Factor-alpha biosynthesis, Tumor Necrosis Factor-alpha chemistry, Aminoquinolines chemical synthesis, Anti-Inflammatory Agents, Non-Steroidal chemical synthesis, Imidazoles chemical synthesis, MAP Kinase Kinase Kinases antagonists & inhibitors, Models, Molecular, Proto-Oncogene Proteins antagonists & inhibitors, Tumor Necrosis Factor-alpha antagonists & inhibitors
- Abstract
Tumor progression loci-2 (Tpl2) (Cot/MAP3K8) is a serine/threonine kinase in the MAP3K family directly upstream of MEK. Recent studies using Tpl2 knockout mice have indicated an important role for Tpl2 in the lipopolysaccharide (LPS) induced production of tumor necrosis factor alpha (TNF-alpha) and other proinflammatory cytokines involved in diseases such as rheumatoid arthritis. Initial 4-anilino-6-aminoquinoline-3-carbonitrile leads showed poor selectivity for Tpl2 over epidermal growth factor receptor (EGFR) kinase. Using molecular modeling and crystallographic data of the EGFR kinase domain with and without an EGFR kinase-specific 4-anilinoquinazoline inhibitor (erlotinib, Tarceva), we hypothesized that we could diminish the inhibition of EGFR kinase by substitution at the C-8 position of our 4-anilino-6-aminoquinoline-3-carbonitrile leads. The 8-substituted-4-anilino-6-aminoquinoline-3-carbonitriles were prepared from the appropriate 2-substituted 4-nitroanilines. Modifications to the C-6 and C-8 positions led to the identification of compounds with increased inhibition of TNF-alpha release from LPS-stimulated rat and human blood, and these analogues were also highly selective for Tpl2 kinase over EGFR kinase. Further structure-activity based modifications led to the identification of 8-bromo-4-(3-chloro-4-fluorophenylamino)-6-[(1-methyl-1H-imidazol-4-yl)methylamino]quinoline-3-carbonitrile, which demonstrated in vitro as well as in vivo efficacy in inhibition of LPS-induced TNF-alpha production.
- Published
- 2007
- Full Text
- View/download PDF
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