Systemic lupus erythematosus (SLE) is a multifaceted autoimmune disorder that manifests through the breakdown of immune tolerance, leading to immune cell hyperactivity, proinflammatory cytokine generation, and end-organ damage due to immune complex accumulation.
Toll-like receptors (TLRs), crucial for innate immune reactions to pathogens and danger signals, are implicated in SLE's development by recognizing self-proteins.
Interleukin receptor-associated kinases (IRAK) 1 and 4 initiate
MyD88-dependent signaling pathways from TLRs and
Interleukin-1 Receptors (IL-1R), making them promising targets for SLE therapy. A phase 1 study has shown that
R835, a potent and selective
IRAK1/4 inhibitor, significantly reduced LPS-induced serum cytokines in healthy volunteers.
The objective of the study was to explore the therapeutic potential of IRAK1/4 inhibition in SLE by assessing the impact of R835 on
TLR7 signaling and its efficacy in a mouse model exhibiting
lupus-like symptoms.
The methodology involved stimulating human primary dendritic cells and whole blood with gardiquimod, a TLR7 agonist, to measure R835's effect on
Interferon-alpha (IFN-α) production. The compound was also tested for its effectiveness on survival and disease progression in lupus-prone NZB/W F1 mice, either at an early stage or with active disease.
The results showed that R835 effectively suppressed TLR7-induced cytokine production in human cells and reduced serum
IFN-α levels in mice in a dose-dependent manner following TLR7 agonist administration. In lupus-prone mice, R835 treatment reversed the progression of the disease and the establishment of a pro-inflammatory environment, evidenced by decreased proteinuria, blood urea nitrogen, autoantibodies, and improved renal pathology.
R835 is the first dual IRAK1/4 inhibitor to enter clinical trials and presents a promising therapeutic approach for autoimmune and rheumatic diseases, including SLE. The study's authors are affiliated with
Rigel Pharmaceuticals, indicating a potential conflict of interest.
How to Use Synapse Database to Search and Analyze Translational Medicine Data?
The transational medicine section of the Synapse database supports searches based on fields such as drug, target, and indication, covering the T0-T3 stages of translation. Additionally, it offers a historical conference search function as well as filtering options, view modes, translation services, and highlights summaries, providing you with a unique search experience.

Taking obesity as an example, select "obesity" under the indication category and click search to enter the Translational Medicine results list page. By clicking on the title, you can directly navigate to the original page.

By clicking the analysis button, you can observe that GLP-1R treatment for obesity has gained significant attention over the past three years, with preclinical research still ongoing in 2023. Additionally, there are emerging potential targets, such as GDF15, among others.

Click on the image below to go directly to the Translational Medicine search interface.
