Small Molecule Degraders of Protein Tyrosine Phosphatase 1B and T‐Cell Protein Tyrosine Phosphatase for Cancer Immunotherapy

Abstract Protein tyrosine phosphatase 1B (PTP1B) and T‐cell protein tyrosine phosphatase (TC‐PTP) play non‐redundant negative regulatory roles in T‐cell activation, tumor antigen presentation, insulin and leptin signaling, and are potential targets for several therapeutic applications. Here, we report the development of a highly potent and selective small molecule degrader DU‐14 for both PTP1B and TC‐PTP. DU‐14 mediated PTP1B and TC‐PTP degradation requires both target protein(s) and VHL E3 ligase engagement and is also ubiquitination‐ and proteasome‐dependent. DU‐14 enhances IFN‐γ induced JAK1/2‐STAT1 pathway activation and promotes MHC‐I expression in tumor cells. DU‐14 also activates CD8 + T‐cells and augments STAT1 and STAT5 phosphorylation. Importantly, DU‐14 induces PTP1B and TC‐PTP degradation in vivo and suppresses MC38 syngeneic tumor growth. The results indicate that DU‐14, as the first PTP1B and TC‐PTP dual degrader, merits further development for treating cancer and other indications.