Systemic lupus erythematosus (SLE), or lupus, takes a devastating toll. An autoimmune disease that triggers a dysfunctional immune system to attack its own tissues, SLE strikes young women most often — about 4 to 12 times more frequently than men — with women aged 15 to 45 being at highest risk. Both genetic and environmental risk factors are suspected.
Widespread tissue damage can affect the joints, kidneys, skin, lungs, brain, and blood vessels. Painful flares can be debilitating, resulting in overwhelming fatigue, rashes, and inflammation and greatly limiting both quality of life and ability to work.
NIK as a Drug Target
The pathogenesis of SLE is mediated by NF-κB-inducing kinase (NIK), which regulates signaling downstream of tumor necrosis factor (TNF) family members. These TNF members include B cell-activating factor (BAFF) and CD40, which are essential for B cell survival and differentiation to auto-antibody-producing plasma cells; TNF-related weak inducer of apoptosis (TWEAK), which controls chronic kidney inflammation and disease that occurs as a consequence of SLE; and the T-cell co-stimulatory molecule OX40L, which expression quantitative trait locus data has shown is highly expressed in people with SLE.,
Identifying small molecule NIK inhibitors is of high interest for development of novel treatments for SLE. Due to increasing prevalence of the disease, the global market for SLE therapeutic agents has been estimated to nearly triple from $1.2 B in 2015 to $3.2 B by 2025.
Search for NIK Inhibitors
A study published by researchers at Genentech describes an analysis for small molecule NIK inhibitors that were tested using a mouse model of SLE. A compound referred to as NIK SMI was identified through a medicinal chemistry optimization program. Brightbill et al. used the Transcreener ADP² Kinase Assay to monitor the ability of NIK to catalyze the hydrolysis of adenosine-5’-triphosphate (ATP) in the presence of test compounds. Tracer displaced by the ADP generated during the NIK reaction caused a decrease in fluorescence polarization that was measured by laser excitation at 633 nm, allowing calculation of equilibrium dissociation constant (Ki) values for the test compounds. The analysis found that NIK SMI1 strongly inhibits human NIK enzymatic activity, and was roughly 1.7-fold less potent when tested with murine NIK.
The authors interpret their in vitro and in vivo data as indicating that inhibition of NIK in the mouse model of SLE mimics the pharmacological effects of BAFF blockade. Blocking BAFF signaling is the premise of belimumab, the only new therapy for lupus that has been approved in half a century. Additionally, NIK inhibition was associated with changes in pro-inflammatory gene expression patterns in the kidney and reduced renal pathology as well as changes in T cell parameters in the spleen.
While more work remains to be done, a strategy to identify additional potential novel SLE drug candidates is an encouraging development. Moving forward will require careful evaluation of NIK inhibitors and other candidates at both the in vitro and in vivo level. Sensitive, HTS-amenable assays play an important role in this process.
– Robyn M. Perrin, PhD
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