Journal
TRANSLATIONAL RESEARCH
Volume 229, Issue -, Pages 69-82Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.trsl.2020.09.003
Keywords
chemical probe; B cell; epigenetics; autoimmune; immune; phenotypic screen
Categories
Funding
- EU/EFPIA Innovative Medicines Initiative Joint Undertaking (ULTRA-DD) [115766]
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The study identified specific epigenetic protein targets that may have potential for treating autoimmune diseases, serving as potential new intervention points for future drug discovery and development efforts.
B-cell secretion of autoantibodies drives autoimmune diseases, including systemic lupus erythematosus and idiopathic inflammatory myositis. Few therapies are presently available for treatment of these patients, often resulting in unsatisfactory effects and helping only some of the patients. We developed a screening assay for evaluation of novel targets suspending B-cell maturation into antibody secreting cells, which could contribute to future drug development. The assay was employed for testing 43 high quality chemical probes and compounds inhibiting under explored protein targets, using primary cells from patients with autoimmune disease. Probes inhibiting bromodomain family proteins and histone methyl transferases demonstrated abrogation of B-cell functions to a degree comparable to a positive control, the JAK inhibitor tofacitinib. Inhibition of each target rendered a specific functional cell and potential disease modifying effect, indicating specific epigenetic protein targets as potential new intervention points for future drug discovery and development efforts.
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