1. Academic Validation
  2. Discovery of a selective TC-PTP degrader for cancer immunotherapy

Discovery of a selective TC-PTP degrader for cancer immunotherapy

  • Chem Sci. 2023 Oct 24;14(44):12606-12614. doi: 10.1039/d3sc04541b.
Jinmin Miao 1 Jiajun Dong 1 Yiming Miao 1 Yunpeng Bai 1 Zihan Qu 2 Brenson A Jassim 1 Bo Huang 2 Quyen Nguyen 2 Yuan Ma 1 Allison A Murray 1 Jinyue Li 1 Philip S Low 2 3 4 Zhong-Yin Zhang 1 2 3 4
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University West Lafayette IN 47907 USA zhang-zy@purdue.edu.
  • 2 Department of Chemistry, Purdue University West Lafayette IN 47907 USA.
  • 3 Institute for Cancer Research, Purdue University West Lafayette IN 47907 USA.
  • 4 Institute for Drug Discovery, Purdue University West Lafayette IN 47907 USA.
Abstract

T-cell protein tyrosine Phosphatase (TC-PTP), encoded by PTPN2, has emerged as a promising target for Cancer Immunotherapy. TC-PTP deletion in B16 melanoma cells promotes tumor cell antigen presentation, while loss of TC-PTP in T-cells enhances T-cell receptor (TCR) signaling and stimulates cell proliferation and activation. Therefore, there is keen interest in developing TC-PTP inhibitors as novel immunotherapeutic agents. Through rational design and systematic screening, we discovered the first highly potent and selective TC-PTP PROTAC degrader, TP1L, which induces degradation of TC-PTP in multiple cell lines with low nanomolar DC50s and >110-fold selectivity over the closely related PTP1B. TP1L elevates the phosphorylation level of TC-PTP substrates including pSTAT1 and pJAK1, while pJAK2, the substrate of PTP1B, is unaffected by the TC-PTP degrader. TP1L also intensifies interferon gamma (IFN-γ) signaling and increases MHC-I expression. In Jurkat cells, TP1L activates TCR signaling through increased phosphorylation of Lck. Furthermore, in a CAR-T cell and KB tumor cell co-culture model, TP1L enhances CAR-T cell mediated tumor killing efficacy through activation of the CAR-T cells. Thus, we surmise that TP1L not only provides a unique opportunity for in-depth interrogation of TC-PTP biology but also serves as an excellent starting point for the development of novel immunotherapeutic agents targeting TC-PTP.

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