Studies of\nStructure–Activity Relationship\nof 2‑(Pyrrolidin-1ylmethyl)‑1<i>H</i>‑pyrrole-Based\nST2 Inhibitors and Their Inhibition of Mast Cells Activation

ST2\nbelongs to the interleukin 1 receptor family and is expressed\nin immune cells including certain CD4<sup>+</sup> T cells and mast\ncells. Binding of ST2 with interleukin 33 (IL-33) induces downstream\nsignaling that activates NF-κB pathway. Although the ST2/IL-33\naxis exerts immune tolerance via expansion of regulator T cells, the\nsame axis also activates a subset of immune cells to produce proinflammatory\ncytokines in host defense or in tissue repair. Here, we reported the\ndevelopment of ST2 inhibitors with improved inhibitory activities\nagainst ST2 and metabolic stability based on a previous lead, <b>iST2-14e</b>. Using the human mast cell line (LAD2), we showed\nthat ST2 inhibitors mitigated ST2 upregulation and reduced IL-1β\nreleased through degranulation, demonstrating that small-molecule\nST2 inhibitors effectively attenuated the ST2/IL-33 signaling in human\nmast cells. Further optimization of the compounds may lay the foundation\nfor developing ST2 inhibitors for the treatment of mast cells mediated\ndiseases.