Discovery of (4-Phenyl-cyclohexyl)acetate-Derived Tyrosylprotein Sulfotransferase 2 (TPST2) Inhibitors with Potent Anti-Tumor Activity for Immuno-Oncology Applications

Abstract

Tyrosylprotein sulfotransferase 2 (TPST2) was recently reported to mediate the post-translational sulfation of interferon γ (IFNγ) receptor, contributing to immunosuppression in tumor microenvironment. Herein, we report the discovery of 77c with an IC<inf>50</inf>value of 946 nM as a novel TPST2 inhibitor through the structure–activity relationship (SAR) studies and optimization of a hit compound, 44a, identified in the enzyme-based screening of 6868 compounds from Korea Chemical Bank (KCB) library. 77c was further evaluated for its binding affinity at TPST2 and effects in IFNγ signaling in cell-based functional assays. In silico docking analysis suggested the putative binding site of 77c and key molecular interactions, providing structural insights into TPST2 inhibition. Furthermore, in the MC38 syngeneic tumor model, 77c significantly suppressed tumor growth and synergized with anti-PD-1 therapy, leading to enhanced T cell-mediated antitumor immunity characterized by increased infiltration of effector CD8+T cells and improved systemic immune activation. © 2025 American Chemical Society