Publications by authors named "Jianmei Wei"

16 Publications

  • Page 1 of 1

Discovery of a Potent and Selective Covalent Inhibitor of Bruton's Tyrosine Kinase with Oral Anti-Inflammatory Activity.

ACS Med Chem Lett 2021 May 5;12(5):782-790. Epub 2021 Apr 5.

Janssen Research & Development, 3210 Merryfield Row, San Diego, California 92121-1126, United States.

Bruton's tyrosine kinase (BTK) is a cytoplasmic tyrosine kinase that plays a critical role in the activation of B cells, macrophages, and osteoclasts. Given the key role of these cell types in the pathology of autoimmune disorders, BTK inhibitors have the potential to improve treatment outcomes in multiple diseases. Herein, we report the discovery and characterization of a novel potent and selective covalent 4-oxo-4,5-dihydro-3-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide BTK inhibitor chemotype. Compound irreversibly inhibits BTK by targeting a noncatalytic cysteine residue (Cys481) for covalent bond formation. Compound is characterized by selectivity for BTK, potent BTK occupancy that is sustained after it is cleared from systemic circulation, and dose-dependent efficacy at reducing joint inflammation in a rat collagen-induced arthritis model.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acsmedchemlett.1c00044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8155241PMC
May 2021

LRRC19 Promotes Permeability of the Gut Epithelial Barrier Through Degrading PKC-ζ and PKCι/λ to Reduce Expression of ZO1, ZO3, and Occludin.

Inflamm Bowel Dis 2021 Jan 27. Epub 2021 Jan 27.

State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China.

Background: A dysfunctional gut epithelial barrier allows the augmented permeation of endotoxins, luminal antigens, and bacteria into the bloodstream, causing disease. The maintenance of gut epithelial barrier integrity may be regulated by multiple factors. Herein we analyze the role of leucine-rich repeat-containing protein 19 (LRRC19) in regulating the permeability of the gut epithelial barrier.

Methods: We utilized Lrrc19 knockout (KO) mice and clinical samples through transmission electron, intestinal permeability assay, Western blot, and immunofluorescence staining to characterize the role of LRRC19 in the permeability of the gut epithelial barrier.

Results: We found that LRRC19, which is expressed in gut epithelial cells, impairs gut barrier function. Transmission electron micrographs revealed a tighter junction and narrower gaps in the colon epithelium cells in LRRC19 KO mice. There were lower levels of serum lipopolysaccharide and 4 kDa-fluorescein isothiocyanate-dextran after gavage in LRRC19 KO mice than in wild-type mice. We found that LRRC19 could reduce the expression of zonula occludens (ZO)-1, ZO-3, and occludin in the colonic epithelial cells. The decreased expression of ZO-1, ZO-3, and occludin was dependent on degrading protein kinase C (PKC) ζ and PKCι/λ through K48 ubiquitination by LRRC19. The expression of LRRC19 was also negatively correlated with ZO-1, ZO-3, occludin, PKCζ, and PKCι/λ in human colorectal cancers.

Conclusions: The protein LRRC19 can promote the permeability of the gut epithelial barrier through degrading PKC ζ and PKCι/λ to reduce the expression of ZO-1, ZO-3, and occludin.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ibd/izaa354DOI Listing
January 2021

LncRNA lncLy6C induced by microbiota metabolite butyrate promotes differentiation of Ly6C to Ly6C macrophages through lncLy6C/C/EBPβ/Nr4A1 axis.

Cell Discov 2020 Nov 24;6(1):87. Epub 2020 Nov 24.

Department of Immunology, Nankai University School of Medicine, Nankai University, Tianjin 300071, China.

Macrophages are mainly divided into two populations, which play a different role in physiological and pathological conditions. The differentiation of these cells may be regulated by transcription factors. However, it is unclear how to modulate these transcription factors to affect differentiation of these cells. Here, we found that lncLy6C, a novel ultraconserved lncRNA, promotes differentiation of Ly6C inflammatory monocytes into Ly6C resident macrophages. We demonstrate that gut microbiota metabolites butyrate upregulates the expression of lncLy6C. LncLy6C deficient mice had markedly increased Ly6C pro-inflammatory monocytes and reduced Ly6C resident macrophages. LncLy6C not only bound with transcription factor C/EBPβ but also bound with multiple lysine methyltransferases of H3K4me3 to specifically promote the enrichment of C/EBPβ and H3K4me3 marks on the promoter region of Nr4A1, which can promote Ly6C into Ly6C macrophages. As a result, lncLy6C causes the upregulation of Nr4A1 to promote Ly6C inflammatory monocytes to differentiate into Ly6C resident macrophages.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41421-020-00211-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7683537PMC
November 2020

Reg4 and complement factor D prevent the overgrowth of E. coli in the mouse gut.

Commun Biol 2020 09 2;3(1):483. Epub 2020 Sep 2.

State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, 300071, China.

The expansion of Enterobacteriaceae, such as E. coli is a main characteristic of gut inflammation and is related to multiple human diseases. However, how to control these E. coli overgrowth is not well understood. Here, we demonstrate that gut complement factor D (CFD) plays an important role in eliminating E. coli. Increased E. coli, which could stimulate inflammatory macrophages to induce colitis, were found in the gut of CFD deficient mice. We also showed that gut Reg4, which is expressed in gut epithelial cells, stimulated complement-mediated attack complexes to eliminate E. coli. Reg4 deficient mice also had increased E. coli. The dominant E. coli were isolated from colitis tissues of mice and found to be sensitive to both CFD- and Reg4-mediated attack complexes. Thus, gut Reg4- and CFD-mediated membrane attack complexes may maintain gut homeostasis by killing inflammatory E. coli.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s42003-020-01219-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7468294PMC
September 2020

The impact of increasing land productivity on groundwater dynamics: a case study of an oasis located at the edge of the Gobi Desert.

Carbon Balance Manag 2020 May 2;15(1). Epub 2020 May 2.

Key Laboratory of Western China's Environmental Systems (Ministry of Education), College of Earth and Environmental Sciences, Lanzhou University, No. 222 South Tainshui Road, Chengguan District, Lanzhou, 730000, Gansu Province, China.

Background: Intensification of agricultural systems may result in overexploitation of water resources in arid regions because enhanced productivity of crops is often associated with increased actual evapotranspiration (AET). The aim of this study was to quantify the effect of increased regional AET on the groundwater level in a case study of the oasis located within the Shiyang River Basin near the edge of the Gobi Desert.

Result: The results of the study show that regional AET increased during the period from 1981 to 2010 due to increasing oasis area and air temperature. The water losses due to AET exceeded the water supply from the mountainous discharges of the basin by the end of this period, leading to groundwater overexploitation in the oasis area.

Conclusions: This case study shows the importance of considering the effect of climate change on water losses associated with increasing agricultural production for the sustainable agricultural development of arid regions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13021-020-00142-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7333277PMC
May 2020

Induction of Inflammatory Macrophages in the Gut and Extra-Gut Tissues by Colitis-Mediated Escherichia coli.

iScience 2019 Nov 26;21:474-489. Epub 2019 Oct 26.

State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin 300071, China; Key Laboratory of Bioactive Materials Ministry of Education, Nankai University, Tianjin 300071, China; Department of Immunology, Nankai University School of Medicine, Nankai University, Tianjin 300071, China. Electronic address:

Inflammatory macrophages play a critical role in gut and extra-gut inflammatory disorders, which may be promoted through the dysbiosis of gut microbiota. However, it is poorly understood how gut microbiota affect inflammatory macrophages. Here, we found that increased Escherichia coli (E. coli) in inflamed colon may induce inflammatory macrophages in gut and extra-gut tissues. These E. coli are different from other commensal and pathogenic E. coli in genomic components and also in ability to induce inflammatory responses. Dominant E. coli from colitic tissues induce gut inflammatory macrophages through a regulating network consisted of IL-18, IFN-γ, IL-12, and IL-22 in gut tissues. These E. coli also directly activate macrophages. Cytosolic inflammasome components PCKδ, NLRC4, caspase8, and caspase1/11 are involved in E. coli-mediated activation in both gut epithelial cells and macrophages. These disclose a novel mechanism for how dysbiosis of gut microbiota in colitis cause inflammatory macrophages related to multiple diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.isci.2019.10.046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6849333PMC
November 2019

Lactobacillus maintains healthy gut mucosa by producing L-Ornithine.

Commun Biol 2019 8;2:171. Epub 2019 May 8.

1State Key Laboratory of Medicinal Chemical Biology, Nankai University, 300071 Tianjin, China.

Gut mucosal layers are crucial in maintaining the gut barrier function. Gut microbiota regulate homeostasis of gut mucosal layer via gut immune cells such as RORγt (+) IL-22(+) ILC3 cells, which can influence the proliferation of mucosal cells and the production of mucin. However, it is unclear how gut microbiota execute this regulation. Here we show that lactobacilli promote gut mucosal formation by producing L-Ornithine from arginine. L-Ornithine increases the level of aryl hydrocarbon receptor ligand L-kynurenine produced from tryptophan metabolism in gut epithelial cells, which in turn increases RORγt (+)IL-22(+) ILC3 cells. Human REG3A transgenic mice show an increased proportion of L-Ornithine producing lactobacilli in the gut contents, suggesting that gut epithelial REG3A favors the expansion of L-Ornithine producing lactobacilli. Our study implicates the importance of a crosstalk between arginine metabolism in Lactobacilli and tryptophan metabolism in gut epithelial cells in maintaining gut barrier.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s42003-019-0424-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6506532PMC
April 2020

The effect of pK(a) on pyrimidine/pyridine-derived histamine H4 ligands.

Bioorg Med Chem Lett 2014 Dec 13;24(23):5489-92. Epub 2014 Oct 13.

Janssen Pharmaceutical Research & Development, LLC, 3210 Merryfield Row, San Diego, CA 92121, United States.

During the course of our efforts toward the discovery of human histamine H4 antagonists from a series of 2-aminiopyrimidines, it was noted that a 6-trifluoromethyl group dramatically reduced affinity of the series toward the histamine H4 receptor. This observation was further investigated by synthesizing a series of ligands that varied in pKa of the pyrimidine derived H4 ligands by over five orders of magnitude and the effect on histamine H4 affinity. This trend was then extended to the discovery of C-linked piperidinyl-2-amino pyridines as histamine H4 receptor antagonists.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2014.10.013DOI Listing
December 2014

Identification of a potent, selective, and orally active leukotriene a4 hydrolase inhibitor with anti-inflammatory activity.

J Med Chem 2008 Jul 28;51(14):4150-69. Epub 2008 Jun 28.

Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 3210 Merryfield Row, San Diego, California 92121, USA.

LTA 4H is a ubiquitously distributed 69 kDa zinc-containing cytosolic enzyme with both hydrolase and aminopeptidase activity. As a hydrolase, LTA 4H stereospecifically catalyzes the transformation of the unstable epoxide LTA 4 to the diol LTB 4, a potent chemoattractant and activator of neutrophils and a chemoattractant of eosinophils, macrophages, mast cells, and T cells. Inhibiting the formation of LTB 4 is expected to be beneficial in the treatment of inflammatory diseases such as inflammatory bowel disease (IBD), asthma, and atherosclerosis. We developed a pharmacophore model using a known inhibitor manually docked into the active site of LTA 4H to identify a subset of compounds for screening. From this work we identified a series of benzoxazole, benzthiazole, and benzimidazole inhibitors. SAR studies resulted in the identification of several potent inhibitors with an appropriate cross-reactivity profile and excellent PK/PD properties. Our efforts focused on further profiling JNJ 27265732, which showed encouraging efficacy in a disease model relevant to IBD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/jm701575kDOI Listing
July 2008

Dual binding site inhibitors of B-RAF kinase.

Bioorg Med Chem Lett 2008 May 4;18(9):2825-9. Epub 2008 Apr 4.

Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.

Computer aided modeling guided the design of a series of diarylimidazole compounds (11-22) intended to interact with both the ATP and adjacent allosteric binding domains of B-RAF kinase. Their ability to inhibit the function of B-RAF kinase and intracellular ERK1/2 phosphorylation were evaluated.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2008.04.002DOI Listing
May 2008

A novel B-RAF inhibitor blocks interleukin-8 (IL-8) synthesis in human melanoma xenografts, revealing IL-8 as a potential pharmacodynamic biomarker.

Mol Cancer Ther 2008 Mar;7(3):492-9

Department of Immunology, Johnson & Johnson Pharmaceutical Research & Development LLC, La Jolla, CA 92121, USA.

B-RAF mutations have been identified in the majority of melanoma and a large fraction of colorectal and papillary thyroid carcinoma. Drug discovery efforts targeting mutated B-RAF have yielded several interesting molecules, and currently, three compounds are undergoing clinical evaluation. Inhibition of B-RAF in animal models leads to a slowing of tumor growth and, in some cases, tumor reduction. Described within is a novel series of diaryl imidazoles with potent, single-digit nanomolar, anti-B-RAF activity. One compound from this series has been detailed here and has been shown to block B-RAF(V600E)-dependent extracellular signal-regulated kinase 1/2 phosphorylation in SK-MEL-28 melanoma cells as well as soft agar colony formation and proliferation. Importantly, interleukin-8 (IL-8) was identified by quantitative real-time PCR and ELISA as a product of the elevated mitogen-activated protein kinase signaling in these cells. Plasma concentrations of IL-8 in mice bearing melanoma xenografts were significantly reduced following exposure to B-RAF inhibitors. Taken together, these data suggest that IL-8 could serve as a tractable clinical biomarker.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1535-7163.MCT-07-0307DOI Listing
March 2008

Pyrazole-based cathepsin S inhibitors with improved cellular potency.

Bioorg Med Chem Lett 2007 Oct 22;17(20):5525-8. Epub 2007 Aug 22.

Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.

High potency pyrazole-based noncovalent inhibitors of human cathepsin S (CatS) were developed by modification of the benzo-fused 5-membered ring heterocycles found in earlier series of CatS inhibitors. Although substitutions on this heterocyclic framework had a moderate impact on enzymatic potency, dramatic effects on cellular activity were observed. Optimization afforded indole- and benzothiophene-derived analogues that were high affinity CatS inhibitors (IC(50)=20-40 nM) with good cellular potency (IC(50)=30-340 nM).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2007.08.038DOI Listing
October 2007

The SAR of 4-substituted (6,6-bicyclic) piperidine cathepsin S inhibitors.

Bioorg Med Chem Lett 2006 Apr 3;16(8):2209-12. Epub 2006 Feb 3.

Johnson and Johnson Pharmaceutical Research and Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.

A series of competitive, reversible cathepsin S (CatS) inhibitors was investigated. An earlier disclosure detailed the discovery of the 4-(2-keto-1-benzimidazolinyl)-piperidin-1-yl moiety as an effective replacement for the 4-arylpiperazin-1-yl group found in our screening hit. Continued investigation into replacements for the 4-aryl piperazine resulted in the identification of potentially useful CatS inhibitors with enzymatic and cellular activity similar to that of JNJ 10329670 as disclosed in a previous publication.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2006.01.038DOI Listing
April 2006

Preparation and biological evaluation of indole, benzimidazole, and thienopyrrole piperazine carboxamides: potent human histamine h(4) antagonists.

J Med Chem 2005 Dec;48(26):8289-98

Johnson & Johnson Pharmaceutical Research and Development, L.L.C., 3210 Merryfield Row, San Diego, California 92121, USA.

Three series of H(4) receptor ligands, derived from indoly-2-yl-(4-methyl-piperazin-1-yl)-methanones, have been synthesized and their structure-activity relationships evaluated for activity at the H(4) receptor in competitive binding and functional assays. In all cases, substitution of small lipophilic groups in the 4 and 5-positions led to increased activity in a [(3)H]histamine radiolabeled ligand competitive binding assay. In vitro metabolism and initial pharmacokinetic studies were performed on selected compounds leading to the identification of indole 8 and benzimidazole 40 as potent H(4) antagonists with the potential for further development. In addition, both 8 and 40 demonstrated efficacy in in vitro mast cell and eosinophil chemotaxis assays.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/jm0502081DOI Listing
December 2005

Discovery and SAR studies of a novel series of noncovalent cathepsin S inhibitors.

Bioorg Med Chem Lett 2005 Mar;15(6):1687-91

Johnson and Johnson Pharmaceutical Research and Development, LLC, 3210 Merryfield Row, San Diego, CA 92121, USA.

A novel series of competitive, reversible cathepsin S (CatS) inhibitors was discovered and optimized. The 4-(2-keto-1-benzimidazolinyl)-piperidin-1-yl moiety was found to be an effective replacement for the 4-arylpiperazin-1-yl group found in our earlier series of CatS inhibitors. This replacement imparted improved PK properties as well as decreased off-target activity. Optimization of the ketobenzimidazole moiety led to the discovery of the lead compound JNJ 10329670, which represents a novel class of selective, noncovalent, reversible, and orally bioavailable inhibitors of cathepsin S.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2005.01.045DOI Listing
March 2005

The first potent and selective non-imidazole human histamine H4 receptor antagonists.

J Med Chem 2003 Sep;46(19):3957-60

Johnson & Johnson Pharmaceutical Research and Development, L.L.C, 3210 Merryfield Row, San Diego, California 92121, USA.

Following the discovery of the human histamine H4 receptor, a high throughput screen of our corporate compound collection identified compound 6 as a potential lead. Investigation of the SAR resulted in the discovery of novel compounds 10e and 10l, which are the first potent and selective histamine H4 receptor antagonists to be described.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/jm0341047DOI Listing
September 2003