Lanraplenib, a selective SYKi, was also shown to retard the progression of LN-like disease in NZB/W mice and reduce glomerular IgG deposition and serum proinflammatory cytokines [102]. long-lived plasma cells, reduced plasmablast differentiation, and production of autoantibodies and interferon-. The sphingosine 1-phosphate/sphingosine 1-phosphate receptor-1 pathway is responsible for lymphocyte trafficking, regulatory T-cell/Th17 cell homeostasis, and vascular permeability. Sphingosine 1-phosphate receptor-1 modulators limit the trafficking of autoreactive lymphocytes across the bloodCbrain barrier, increase regulatory T-cell function, and decrease production of autoantibodies and type I interferons. This article summarizes the development of these targeted small molecules in the treatment of systemic lupus erythematosus, and the future prospect for precision medicine. Key Points Small molecules that target the Janus kinases, Brutons tyrosine kinases, spleen tyrosine kinases, immunoproteasomes, cereblon, and sphingosine 1-phosphate receptor-1 are developed for the treatment of malignant and autoimmune disorders, including systemic lupus erythematosus.These targeted small molecules have the advantages of convenient administration, lower production costs, Clomipramine HCl and the lack of immunogenicity.Some of these compounds, such as deucravacitinib, orelabrutinib, and iberdomide, have shown promise in phase II trials. Other small molecules, zetomipzomib and cenerimod, LANCL1 antibody are undergoing phase II/III trials in systemic lupus erythematosus and lupus nephritis.Genetic and molecular profiling may help stratify patients to choose the most appropriate targeted therapies in future.With more treatment modalities available for systemic lupus erythematosus, the treat-to-target approach is increasingly feasible in clinical practice. Open in a separate window Introduction Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease characterized by an unpredictable clinical course with periods of exacerbation and remission. The pathogenesis of SLE remains elusive, and multiple genetic, epigenetic, environmental, and hormonal factors contribute to loss of self-tolerance and aberration of the adaptive and innate immune systems [1, 2]. Clearance of apoptotic materials, nuclear antigens, nucleosomes, and immune complexes by macrophages and complements is defective in SLE [3]. In addition, dysregulated neutrophil apoptosis and inefficient degradation of the neutrophil extracellular traps that contain DNA, histones, cytoplasmic granules, and other mediators in SLE increase the burden of nuclear autoantigens to the immune system [3C6]. Interaction of excessive apoptotic materials and immune complexes with the toll-like receptors (TLRs) 7/9 leads to the activation of the plasmacytoid dendritic cells (pDCs) and release of type I interferons (IFNs) and interleukin (IL)-6, which in turn enhance monocyte maturation, impair apoptosis of T cells, and activate B-cell proliferation and autoantibody production [7C9]. Increased maturation of myeloid dendritic cells in SLE promotes IL-17 production by T cells [10] and the defective functions of the regulatory T cells (Tregs) and B cells also contributes to hyperactivity of the immune cells [11, 12]. Cytokines are secreted by cells of the immune systems for mutual communication and orchestration of the immune response [13], and may exhibit proinflammatory or anti-inflammatory properties, or both, depending on the microenvironment [14]. Production of cytokines is dysregulated in SLE, which may either be the primary pathogenetic process or secondary to the imbalance of immune pathways, such as the Th1/Th2 and Th17/Treg [15]. Patients with SLE have abnormal expression or levels of serum cytokines, such as the IFNs (IFN, IFN), ILs (IL-2, IL-6, IL-10, IL-12, IL-15, IL-17, IL-21, IL-23), and B-cell activation factor (BAFF) [14]. The peripheral blood BAFF and IFN gene signatures of patients with SLE correlate with disease activity, particularly musculoskeletal and dermatological disease [16C18]. The dysregulation of the cytokine network contributes to inhibition of Treg activity but promotion of MHC expression, Th17 differentiation, T/B-cell activation and survival, and autoantibody production [15]. The increased knowledge of the intracellular mechanisms has led to Clomipramine HCl the development of novel agents for the treatment of autoimmune diseases, including SLE. Inhibition of the receptor-associated Janus kinases (JAKs) provides a novel approach in suppressing the downstream signals of multiple cytokines and growth factors [1]. Suppression of the intracellular Brutons tyrosine kinase (BTK) and spleen tyrosine kinase (SYK), which are cytosolic non-receptor proteins essential for B-cell receptor signaling, leads to impaired B-cell activation, Clomipramine HCl differentiation, and survival, as well as expression of the costimulatory molecules, and production of antibodies and cytokines [19, 20]. This BTK/SYK inhibition also affects the functions of other immune cell types such as the macrophages, neutrophils, mast cells, and.