Discovery of Lanraplenib (GS-9876): A Once-Daily Spleen Tyrosine Kinase Inhibitor for Autoimmune Diseases

Blomgren, Peter; Chandrasekhar, Jayaraman; Paolo, Julie A. Di; Fung, Wanchi; Geng, Guoju; Ip, Carmen; Jones, Randall M.; Kropf, Jeffrey E.; Lansdon, E.B.; Lee, Seung; Lo, Jennifer R; Mitchell, Scott A.; Murray, Bernard P.; Pohlmeyer, Chris; Schmitt, Aaron C.; Suekawa-Pirrone, K.; Wise, Sarah; Xiong, Jin-Ming; Xu, Jianjun; Yu, Helen; Zhao, Zheng; Currie, Kevin S.

doi:10.1021/acsmedchemlett.9b00621

Cited by 30 publications

(28 citation statements)

References 27 publications

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“…Other treatments targeting TLRs or IFN-I downstream pathways included Syk inhibitors, Tyk2 inhibitors, TLR7, nine inhibitors, and IRF inhibitors (Chasset and Arnaud, 2018;Goess et al, 2019;Haselmayer et al, 2019;Blomgren et al, 2020;Jiang et al, 2020;Lorenzo-Vizcaya et al, 2020;Song et al, 2020), but most of these molecules are at most in early phase 2 development.…”

Section: Other Treatmentsmentioning

confidence: 99%

Type I Interferons in Systemic Autoimmune Diseases: Distinguishing Between Afferent and Efferent Functions for Precision Medicine and Individualized Treatment

2021

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A sustained increase in type I interferon (IFN-I) may accompany clinical manifestations and disease activity in systemic autoimmune diseases (SADs). Despite the very frequent presence of IFN-I in SADs, clinical manifestations are extremely varied between and within SADs. The present short review will address the following key questions associated with high IFN-I in SADs in the perspective of precision medicine. 1) What are the mechanisms leading to high IFN-I? 2) What are the predisposing conditions favoring high IFN-I production? 3) What is the role of IFN-I in the development of distinct clinical manifestations within SADs? 4) Would therapeutic strategies targeting IFN-I be helpful in controlling or even preventing SADs? In answering these questions, we will underlie areas of incertitude and the intertwined role of autoantibodies, immune complexes, and neutrophils.

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Section: Other Treatmentsmentioning

confidence: 99%

Type I Interferons in Systemic Autoimmune Diseases: Distinguishing Between Afferent and Efferent Functions for Precision Medicine and Individualized Treatment

2021

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“…It is now possible to reconstitute many of the cell types and processes that constitute our immune systems in culture, but a comprehensive panel of assays is required ( Figure 4 ). On this point, it is instructive to read papers from pharmaceutical companies which report comprehensive immuno-profiling of small-molecule immunomodulators, such as kinase inhibitors, using a battery of assays with multiple immune cell types, inputs and outputs ( Braselmann et al, 2006 ; Zhu et al, 2007 ; Blomgren et al, 2020 ).…”

Section: Strategies To Elucidate Tcm Activities and Identify New Drug Leadsmentioning

confidence: 99%

Immunomodulatory drug discovery from herbal medicines: Insights from organ-specific activity and xenobiotic defenses

Shi

Weng

Mitchison

2021

eLife

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Traditional herbal medicines, which emphasize a holistic, patient-centric view of disease treatment, provide an exciting starting point for discovery of new immunomodulatory drugs. Progress on identification of herbal molecules with proven single agent activity has been slow, in part because of insufficient consideration of pharmacology fundamentals. Many molecules derived from medicinal plants exhibit low oral bioavailability and rapid clearance, leading to low systemic exposure. Recent research suggests that such molecules can act locally in the gut or liver to activate xenobiotic defense pathways that trigger beneficial systemic effects on the immune system. We discuss this hypothesis in the context of four plant-derived molecules with immunomodulatory activity: indigo, polysaccharides, colchicine, and ginsenosides. We end by proposing research strategies for identification of novel immunomodulatory drugs from herbal medicine sources that are informed by the possibility of local action in the gut or liver, leading to generation of systemic immune mediators.

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“…Lanraplenib is a novel, selective, oral, once-daily intracellular SYK inhibitor [ 33 ]. In the current study, we examined the effects of lanraplenib on primary human B cell functionality and LN-like disease progression in the NZB/W murine model.…”

Section: Introductionmentioning

confidence: 99%

Characterization of the mechanism of action of lanraplenib, a novel spleen tyrosine kinase inhibitor, in models of lupus nephritis

et al. 2021

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Background B cells are critical mediators of systemic lupus erythematosus (SLE) and lupus nephritis (LN), and antinuclear antibodies can be found in the serum of approximately 98% of patients with SLE. Spleen tyrosine kinase (SYK) is a nonreceptor tyrosine kinase that mediates signaling from immunoreceptors, including the B cell receptor. Active, phosphorylated SYK has been observed in tissues from patients with SLE or cutaneous lupus erythematosus, and its inhibition is hypothesized to ameliorate disease pathogenesis. We sought to evaluate the efficacy and characterize the mechanism of action of lanraplenib, a selective oral SYK inhibitor, in the New Zealand black/white (NZB/W) murine model of SLE and LN. Methods Lanraplenib was evaluated for inhibition of primary human B cell functions in vitro. Furthermore, the effect of SYK inhibition on ameliorating LN-like disease in vivo was determined by treating NZB/W mice with lanraplenib, cyclophosphamide, or a vehicle control. Glomerulopathy and immunoglobulin G (IgG) deposition were quantified in kidneys. The concentration of proinflammatory cytokines was measured in serum. Splenocytes were analyzed by flow cytometry for B cell maturation and T cell memory maturation, and the presence of T follicular helper and dendritic cells. Results In human B cells in vitro, lanraplenib inhibited B cell activating factor-mediated survival as well as activation, maturation, and immunoglobulin M production. Treatment of NZB/W mice with lanraplenib improved overall survival, prevented the development of proteinuria, and reduced blood urea nitrogen concentrations. Kidney morphology was significantly preserved by treatment with lanraplenib as measured by glomerular diameter, protein cast severity, interstitial inflammation, vasculitis, and frequency of glomerular crescents; treatment with lanraplenib reduced glomerular IgG deposition. Mice treated with lanraplenib had reduced concentrations of serum proinflammatory cytokines. Lanraplenib blocked disease-driven B cell maturation and T cell memory maturation in the spleen. Conclusions Lanraplenib blocked the progression of LN-like disease in NZB/W mice. Human in vitro and murine in vivo data suggest that lanraplenib may be efficacious in preventing disease progression in patients with LN at least in part by inhibiting B cell maturation. These data provide additional rationale for the use of lanraplenib in the treatment of SLE and LN.

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Discovery of Lanraplenib (GS-9876): A Once-Daily Spleen Tyrosine Kinase Inhibitor for Autoimmune Diseases

Cited by 30 publications

References 27 publications

Type I Interferons in Systemic Autoimmune Diseases: Distinguishing Between Afferent and Efferent Functions for Precision Medicine and Individualized Treatment

Type I Interferons in Systemic Autoimmune Diseases: Distinguishing Between Afferent and Efferent Functions for Precision Medicine and Individualized Treatment

Immunomodulatory drug discovery from herbal medicines: Insights from organ-specific activity and xenobiotic defenses

Characterization of the mechanism of action of lanraplenib, a novel spleen tyrosine kinase inhibitor, in models of lupus nephritis

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