JAK3 is predominantly expressed in hematopoietic cells and has been a promising therapeutic target for the treatment of B-cell lymphoma. In this study, a new class of thieno[3,2-d]pyrimidines harboring acrylamide pharmacophore were synthesized as potent covalent JAK3 inhibitors (IC < 10 nM). Among them, 9a and 9 g displayed the strongest inhibitory potency against JAK3 kinase activity, with IC values of 1.9 nM and 1.8 nM, respectively. Furthermore, compared with the reference agents, Spebrutinib and Ibrutinib, 9a not only demonstrated enhanced antiproliferative activity against B lymphoma cells, but also showed very weak proliferative inhibition against normal peripheral blood mononuclear cells (PBMCs) at a concentration of 20 μM. Analysis of the mechanism revealed that 9a could induce the obvious apoptosis in B lymphoma cells and prevent JAK3-STAT3 cascade as well as BTK pathway. Taken together, 9a may be served as a potential new JAK3 inhibitor for the treatment of B-cell lymphoma.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1016/j.bioorg.2019.103542 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
The Stability-Indicating Ultra High-Performance Liquid Chromatography with Diode Array Detector and Tandem Mass Spectrometry Method Applied for the Forced Degradation Study of Ritlecitinib: An Appraisal of Green and Blue Metrics.
Pharmaceuticals (Basel)
January 2025
Department of Pharmaceutical Analysis, Faculty of Pharmacy and Biochemistry, University of Zagreb, 10000 Zagreb, Croatia.
Background/objectives: Janus kinase inhibitors open new horizons for small-molecule drugs in treating inflammatory bowel disease, with ritlecitinib demonstrating significant efficacy in clinical trials for ulcerative colitis and Crohn's disease. Ritlecitinib, a second-generation JAK3 inhibitor, is a novel therapeutic agent for alopecia areata and other autoimmune conditions.
Methods: A new stability-indicating UHPLC-DAD-MS/MS method was developed, validated, and applied for a forced degradation study of ritlecitinib under ICH guidelines.
Ritlecitinib, a JAK3 /TEC inhibitor, modulates the markers of celiac autoimmunity in alopecia areata and vitiligo patients.
Arch Dermatol Res
January 2025
Division of Gastroenterology and Hepatology, 200 1st Street SW, Rochester, MN, 55905, USA.
Background: Celiac disease (CeD) has shown an association with autoimmune disorders including vitiligo and alopecia areata (AA). Ritlecitinib, a JAK3 and TEC kinase family inhibitor, has been approved for treatment of patients with AA and is in late-stage development for vitiligo. Ritlecitinib inhibits cytotoxic T cells, NK cells, and B cells which play a role in the pathogenesis of CeD.
View Article and Find Full Text PDFJAK3 Inhibitors: Covalent and Noncovalent Interactions of a Cyanamide Group Investigated by Multiscale Free-Energy Simulations.
J Chem Inf Model
January 2025
Medicinal Chemistry and Drug Design Technologies Department, Chiesi Farmaceutici S.p.A., Largo F. Belloli 11/A, 43122 Parma, Italy.
Janus kinase type 3 (JAK3), an emerging target for treating autoimmune diseases, possesses a front pocket cysteine that is targeted by covalent modifiers, best represented by the marketed drug ritlecitinib (). Recently, 2,3-dihydro-1-inden-1-ylcyanamides have been developed as novel JAK3 inhibitors. Among them, the -(6-(7-pyrrolo[2,3-]pyrimidin-4-yl)-2,3-dihydro-1-inden-1-yl)cyanamide inhibitor () and its methylated analogue (), while being potent inhibitors, displayed different mechanisms of action (covalent vs noncovalent) and binding modes (Casimiro-Garcia et al.
View Article and Find Full Text PDFUsing patient preference to inform ritlecitinib dose selection for alopecia areata treatment.
J Dermatol
January 2025
Pfizer, Groton, Connecticut, USA.
Ritlecitinib is an oral Janus kinase 3/tyrosine kinase expressed in hepatocellular carcinoma (JAK3/TEC) family kinase inhibitor approved for the treatment of severe alopecia areata (AA). Benefit-risk profiles of two doses of ritlecitinib (50 mg vs 30 mg once daily) were evaluated by integrating patient preferences and clinical efficacy and safety estimates for ritlecitinib. A discrete-choice experiment (DCE) was utilized to elicit preferences for benefit and safety attributes of systemic AA treatments.
View Article and Find Full Text PDFUnderstanding Cardiovascular Events With JAK Inhibitors: Tofacitinib Reduces Synovial and Vascular Inflammation but not the Prothrombotic Effects of Inflammatory Cytokines on Endothelium.
ACR Open Rheumatol
January 2025
Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France.
Objective: Inflammation drives cardiovascular disease in rheumatoid arthritis (RA). Treatment with tofacitinib, a JAK1/JAK3 inhibitor, is associated with increased cardiovascular events in patients with RA. Here, we determined its effects on cytokine production during interactions between immune cells at the synovial and vascular levels and its impact on endothelial activation and coagulation during inflammation.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!