Summary

Target is a novel GPCR required for humoral immune responses, and its single nucleotide polymorphisms (SNPs) have been identified to be associated with inflammatory autoimmune diseases. IPG11406, a highly potent small molecule and target antagonist, exhibits good aqueous solubility, excellent selectivity, and favorable pharmacokinetic properties. Moreover, it has demonstrated exceptional efficacy in multiple preclinical disease models, including murine collagen-induced arthritis (CIA) as a model for rheumatoid arthritis (RA), murine experimental autoimmune encephalomyelitis (EAE) for multiple sclerosis (MS), murine IL10^-/- model for inflammatory bowel disease (IBD), and murine MLR/lpr model for systemic lupus erythematosus (SLE). In these models, IPG11406 achieved efficacy with a dose of 0.1 mg/kg, significantly reducing symptoms of organ involvement, proinflammatory cytokine gene expression, and inflammatory cell infiltration.

Moreover, IPG11406 exhibits an excellent profile of in vitro and in vivo preclinical pharmacology and pharmacokinetics (PK). Its promising results led to IND approval for multiple autoimmune disease indications from both the FDA and NMPA, and it is currently being advanced into human clinical trials. IPG11406 holds great promise as a disease-modifying drug for autoimmune diseases.  

Mechanism of Action

￭ Inflammatory lesions generated higher concentrations of TARGET ligands.

￭ TARGET-positive immune cells respond to their ligands by migrating toward the lesion sites.

￭ Immune cells within inflammatory lesions secrete increased levels of cytokines, thereby amplifying the inflammatory and exacerbating the autoimmune disease.

￭ IPG11406 exerts its effect by effectively inhibiting immune cell migration and proliferation at the lesion site, attenuating pathogenesis.  

Key Differentiation

￭ IPG11406 is a potential disease-modifying drug; this targeted approach may confer greater effectiveness than biologics that target individual cytokines.

￭ IPG11406 exhibits efficacy in multiple animal models with very low doses and a safety margin exceeding 150-fold, which may offer a safer alternative to steroid medications and JAK inhibitors.

In vitro and In vivo Properties

In vitro:

￭IPG11406 inhibits TARGET-mediated β-arrestin activation (IC50 = 6.5 nM).

￭IPG11406 suppresses TARGET-mediated migration of U937 and Th17 cells (IC50 = 5.5 and 3.8 nM, respectively).

In vivo:

￭ IPG11406 reduces CD11b+ cell infiltration in colon tissues of Il10^-/- mice.

￭  IPG11406 attenuates immune reactions in the cecum of Il10^-/- mice

Publications 

￭Xi et al., Compound 32 discovered as a potential TARGET antagonist for treating rheumatoid arthritis (J. Medicinal Chemistry, In press).

￭Li et al., IPG11406, a TARGET inhibitor, improves IBD pathologies in Il10^-/- mice by reducing macrophage and Th1 cell infiltration in the intestine (drafting).

￭ Gong et al., Therapeutic potential of a TARGET antagonistic small molecule for systemic lupus erythematosus (under review).