QP6126, an orally bioavailable QPCTL inhibitor, with anti-tumor activity in melanoma tumor model.

Glutaminyl-peptide cyclotransferase-like protein (QPCTL) is a pivotal post-translational modification enzyme remodeling tumor microenvironment through catalyzing the pyroglutamation (pGlu) at the N-terminus of CD47, CCL2 and CCL7. Inhibiting QPCTL attenuates the CD47-SIRPα interaction and impairs the recruitment of pro-tumoral macrophages, thereby promoting anti-tumor immunity, and has emerged as a potential target for cancer immunotherapy. Nevertheless, the development of QPCTL inhibitors for cancer immunotherapy is still in its early stages. Herein, we report the discovery and characterization of QP6126, a highly potent and orally bioavailable small-molecule QPCTL inhibitor (IC50 of 2.3 nM). Mechanistically, QP6126 effectively ablates the pGlu-CD47 modification, thereby abolishing CD47-SIRPα interaction, and sensitizing melanoma cells to macrophage-mediated phagocytosis. Notably, QP6126 displays significant in vivo antitumor efficacy in B16F10 melanoma mouse model following oral administration. This study establishes QP6126 as a promising candidate for clinical translation and validate QPCTL as a strategic target for diversifying cancer immunotherapy.