Journal article
Small Molecule Degraders of Protein Tyrosine Phosphatase 1B and T-Cell Protein Tyrosine Phosphatase for Cancer Immunotherapy
J Dong, J Miao, Y Miao, Z Qu, S Zhang, P Zhu, F Wiede, BA Jassim, Y Bai, Q Nguyen, J Lin, L Chen, T Tiganis, WA Tao, ZY Zhang
Angewandte Chemie International Edition | WILEY-V C H VERLAG GMBH | Published : 2023
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 ..
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Awarded by National Institutes of Health
Funding Acknowledgements
This work was supported in part by NIH RO1CA069202 and the Robert C. and Charlotte Anderson Chair Endowment (to Z.-Y.Z.), NIH 3RF1AG064250 (to W.A.T.), the National Health and Medical Research Council of Australia (to T.T.) and Cancer Council Victoria (to F.W.). The authors gratefully acknowledge the support of NIH P30 CA023168 for use of the Flow Cytometry Facility.