Studies of Structure–Activity Relationship of 2-(Pyrrolidin-1ylmethyl)-1<i>H</i>-pyrrole-Based ST2 Inhibitors and Their Inhibition of Mast Cells Activation

ST2 belongs to the interleukin 1 receptor family and is expressed in immune cells including certain CD4⁺ T cells and mast cells. Binding of ST2 with interleukin 33 (IL-33) induces downstream signaling that activates NF-κB pathway. Although the ST2/IL-33 axis exerts immune tolerance via expansion of regulator T cells, the same axis also activates a subset of immune cells to produce proinflammatory cytokines in host defense or in tissue repair. Here, we reported the development of ST2 inhibitors with improved inhibitory activities against ST2 and metabolic stability based on a previous lead, <b>iST2-14e</b>. Using the human mast cell line (LAD2), we showed that ST2 inhibitors mitigated ST2 upregulation and reduced IL-1β released through degranulation, demonstrating that small-molecule ST2 inhibitors effectively attenuated the ST2/IL-33 signaling in human mast cells. Further optimization of the compounds may lay the foundation for developing ST2 inhibitors for the treatment of mast cells mediated diseases.