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  3. Small Molecule Degraders of Protein Tyrosine Phosphatase 1B and T-Cell Protein Tyrosine Phosphatase for Cancer Immunotherapy

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

  • Angew Chem Int Ed Engl. 2023 May 22;62(22):e202303818. doi: 10.1002/anie.202303818.
Jiajun Dong 1,  Jinmin Miao 1,  Yiming Miao 1,  Zihan Qu 2,  Sheng Zhang 1,  Peipei Zhu 3,  Florian Wiede 4 5,  Brenson A Jassim 1,  Yunpeng Bai 1,  Quyen Nguyen 2,  Jianping Lin 1,  Lan Chen 6,  Tony Tiganis 4 5,  W Andy Tao 2 3 7 6,  Zhong-Yin Zhang 1 2 3 7 6
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, USA.
  • 2 Department of Chemistry, Purdue University, West Lafayette, IN 47907, USA.
  • 3 Department of Biochemistry, Purdue University, West Lafayette, IN 47907, USA.
  • 4 Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria, 3800, Australia.
  • 5 Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, 3800, Australia.
  • 6 Institute for Drug Discovery, Purdue University, West Lafayette, IN 47907, USA.
  • 7 Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA.
PMID: 36973833 DOI: 10.1002/anie.202303818
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.

Keywords

Immunotherapy; PROTAC Degrader; PTP1B; TC-PTP.

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