Substituted 2-pyrrolinone compounds as inhibitors of B-cell activating factor (BAFF) for autoimmune diseases treatment.

B-cell activating factor (BAFF) is a cytokine that plays a critical role in the proliferation and differentiation of B cells. We have previously demonstrated that its inherited overexpression is associated with increased circulating B cell and immunoglobulin levels, correlating with increased risk of multiple sclerosis and systemic lupus erythematosus. These findings suggest that enhanced BAFF expression may be involved in the causal biology of these disorders, thus supporting the rationale for therapeutic inhibition of this cytokine. However, to date, no small-molecule modulator capable of inhibiting BAFF is available. We therefore employed a virtual screening approach to analyze a library of 275,561 small molecules, followed by in vitro validation of 218 selected compounds with potential to disrupt the interaction between BAFF and its receptor BAFFR. Our results identified two promising small molecules, C45 and C145, belonging to the substituted 2-pyrrolinone family, which effectively inhibited BAFF activity. These compounds warrant further investigation as potential therapeutic agents for BAFF-driven autoimmune diseases.