BI-2253

BI-2253 is a highly potent and selective small molecule inhibitor of glutaminyl-peptide cyclotransferase (QPCT) and glutaminyl-peptide cyclotransferase-like protein (QPCTL), collectively referred to as QPCT/L. Developed by Boehringer Ingelheim, BI-2253 is being investigated for the treatment of interstitial lung diseases (ILDs), including pulmonary fibrosis. QPCT/L enzymes catalyze the post-translational N-terminal pyroglutamation of target proteins, such as CD47, which regulates its interaction with SIRPα and mediates the 'don't eat me' signal. By inhibiting QPCT/L, BI-2253 enhances CD47-driven efferocytosis, promoting the clearance of senescent cells and apoptotic corpses by macrophages, thereby demonstrating robust anti-fibrotic effects. However, preclinical studies in bleomycin-induced lung fibrosis models have shown a bell-shaped dose-response curve, where high doses of BI-2253 trigger cytotoxic CD8+ T cell activation and an interferon-gamma (IFN-γ) response, which can worsen inflammation and offset therapeutic benefits.