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

An inhibitor for protein tyrosine phosphatase 1B (PTP1B) and T-cell protein tyrosine phosphatase (TC-PTP) was discovered and transformed into a first-in-class, potent, and selective dual PROTAC degrader for both targets. The degrader promotes antigen presentation of tumor cells and activates CD8+ T-cells. Importantly, the degrader is effective in vivo and suppresses syngeneic tumor growth.

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.

Zum Volltext