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
  • 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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