A Small Molecule Strategy to Safely Mimic Glucocorticoids by Enhancing GILZ

Glucocorticoids (GCs) are nearly universally used to manage lupus due to their potent anti-inflammatory effects, but they come with a significant cost. Long-term use of GCs can lead to severe side effects and an increased risk of infections. Finding safer alternatives to GCs is a top priority in lupus research. With previous LRA funding, Associate Professor Jones and LRA-funded investigator Professor Eric Morand identified a promising alternative in a protein called GILZ (glucocorticoid-induced leucine zipper). GILZ offers many of the anti-inflammatory benefits of GCs but without the harmful metabolic side effects associated with steroid use, making it an ideal target for a safer, more effective steroid-like therapy.

To boost the body’s levels of GILZ, the team is working to block a specific protein called an E3 ubiquitin ligase (“E3-X”), which limits the amount of GILZ by breaking it down. Preliminary data from human cell lines and a mouse model have shown that when E3-X is blocked, GILZ levels rise significantly, mimicking the anti-inflammatory effects of GCs. These previous studies also demonstrated that inhibiting E3-X reduces the production of inflammatory molecules (particularly type I interferons), decreases the activation of overactive immune cells, and makes the cells more sensitive to GC treatment. Dr. Jones will now develop assays (laboratory tests) to screen for small molecules that block E3-X, with the goal of creating an oral therapy for lupus patients. If successful, this paradigm-shifting approach could lead to a new alternative for people with lupus that delivers the benefits of steroids without the dangerous side effects.

What this means for people with lupus

Findings from Dr. Jones’ project could revolutionize lupus treatment, offering a steroid-free alternative that reduces inflammation without the harmful long-term effects of current therapies. This would not only improve the quality of life for lupus patients but also reduce the risk of complications associated with prolonged steroid use.

The use of glucocorticoids (GC) is a pillar of modern medicine, relied upon daily in millions of patients worldwide for their broad suppressive effects on harmful inflammatory pathways. However, GC also cause predictable harmful metabolic side effects, driven by supraphysiological concentrations acting on the GC receptor (GR). Despite advances in care, 80% of patients with systemic lupus erythematosus (SLE) remain chronically treated with GC. The discovery of a safe and effective replacement for GC represents a major unmet need for medicine. It is with the ambition to meet this need that PI Jones has built her group, in the department of co-investigator Morand, which has focused for >20 years on the problems of GC adverse effects in medicine. We have made a series of fundamental novel observations that have the potential to transform this scientific field and yield extraordinary translational and commercialisation outcomes, by identifying GC-induced leucine zipper (GILZ; TSC22D3) as a powerful GC mimic, which does not transduce metabolic harmful effects, and which can be regulated by GR-independent pathways. We have shown that GILZ has similar anti-inflammatory effects to GC in a wide range of immune cells and in vivo model; our novel studies also demonstrate that GILZ is not involved in the metabolic adverse effects of GC. Moreover, GC sensitivity is suppressed by type I interferon (IFN) in SLE patients; we now know that this involves direct suppression of GILZ by IFN. We discovered a means to therapeutically enhance GILZ, via small molecule inhibition of a specific E3 ligase, “E3-X”. E3-X inhibition using human cell lines and a knockout mouse strain has shown that GILZ half life is more than doubled, and GILZ abundance is correspondingly increased when E3-X is blocked, similar to the effect of GC. E3-X inhibition reduced inflammatory cytokine production including type I interferon, inhibited T and B cell and monocyte, dendritic cell and plasmacytoid dendritic cell activation, lowered inflammation in acute and chronic inflammation mouse models, and showed a tenfold steroid-sparing effect. These effects together demonstrate the broad efficacy of our immunomodulatory approach. This grant will fund the development of in vitro and cellular assays to enable the screening funnel and hit to lead work. Hits and/or early lead compounds will be developed in parallel which will be profiled by these assays. The assay results will be used with iterative rounds of resynthesis to give optimized compounds. This plan is informed by extensive discussions with potential industry partners, investors and consultants, which incorporated feasibility assessments, modelling and experienced feedback.