Journal: Journal of Medicinal Chemistry
Article Title: A Rationally Designed Novel Bifunctional Human TNF-α- and Janus Kinase-Targeted soloMER Drug Conjugate (SDC) with a Neutrophil Elastase Cleavable Linker Delivering Inflammation Site-Specific Release of Payload
doi: 10.1021/acs.jmedchem.6c00532
Figure Lengend Snippet: Efficacy of ELN28-135-01 in a Tg197 transgenic mouse model of arthritis. Tg197 mice were treated with ELN22-108, ELN28-135-01, and ELN0-2V-135-01 for 7 weeks starting at week 3. Effect of test articles on (A) in vivo arthritic score, (B) inflammation score, (C) cartilage destruction score, (D) bone erosion score, and (E) total histopathology score. (F) Mouse CXCL1 and (G) MCP-1 protein levels in serum. (H) 2D scatterplots comparing gene expression modulation. (I) Restoration of expression levels (gene counts) for genes involved in the JAK/STAT signaling pathway. Data for the arthritic score are presented as mean ± SEM ( n = 10). For the rest of panels, data are presented as a scatter plot, with the median indicated by a line ( n = 8). Statistical significance was assessed using an unpaired t -test with Welch’s correction (*, p <0.05).
Article Snippet: Actinomycin D (1229, R&D Systems), Healthy human PBMCs (Precision Medicine), HEK Blue Reporter Assay IL23 (hkb-il23, InvivoGen), HEK Blue Reporter Assay IL12 (hkb-il12, InvivoGen), L929 (Sigma), human IL23 (1290-IL/CF, R&D Systems), cynomolgus IL12 (10215-CL, R&D systems), human neutrophil elastase (324681, Merck), human TNF-α (TNFA-HA4211, Acro Bioscience), Phytohemagglutinin-L (PHA) (11249738001, Sigma), QUANTI-Blue solution (rep-qbs, InvivoGen), tofacitinib (FT32555, Biosynth), WST-1 reagent (11644807001, Merck), mIL-6 (Quantikine ELISA, M6000B, R&D Systems), MCP-1 (Quantikine ELISA, JE00B, R&D Systems), and CXCL1 (DuoSet ELISA, DY453, R&D Systems).
Techniques: Transgenic Assay, In Vivo, Histopathology, Gene Expression, Expressing
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