Unique Polypharmacology Nuclear Receptor Modulator Blocks Inflammatory Signaling Pathways

Area of Science:

• Immunology
• Metabolic disease research
• Pharmacology

Background:

• Obesity and rheumatic diseases share underlying chronic inflammation.
• TREM-1 (triggering receptor expressed on myeloid cells-1) amplifies inflammatory responses.
• Existing treatments often target single pathways, necessitating broader approaches.

Purpose of the Study:

• To investigate the efficacy of SR1903, a pan modulator, in preclinical models of inflammation and metabolic dysfunction.
• To characterize the polypharmacological profile of SR1903, including its activity on RORγ, LXR, and PPARγ.
• To evaluate the therapeutic potential of SR1903 for treating interconnected inflammatory and metabolic disorders.

Main Methods:

• Utilized collagen-induced arthritis and diet-induced obesity mouse models.
• Assessed the impact of SR1903 on TREM-1 activation and inflammatory markers.
• Evaluated SR1903's effects on thymic homeostasis and LPS signaling.
• Characterized SR1903's activity across RORγ, LXR, and PPARγ receptors.

Main Results:

• SR1903 demonstrated significant anti-inflammatory and anti-diabetic effects in mouse models.
• The compound effectively blocked TREM-1 activation and LPS signaling.
• SR1903 maintained thymic homeostasis in obese mice, unlike selective RORγ inverse agonists.
• SR1903 was well-tolerated upon chronic administration.

Conclusions:

• SR1903 is a unique polypharmacological modulator with potential for treating linked metabolic and inflammatory diseases.
• Blocking TREM-1 and modulating RORγ, LXR, and PPARγ offers a promising therapeutic strategy.
• SR1903's ability to impact innate immune responses warrants further investigation for related disorders.