2. Academic Validation
  3. Discovery of PVD-06 as a Subtype-Selective and Efficient PTPN2 Degrader

Discovery of PVD-06 as a Subtype-Selective and Efficient PTPN2 Degrader

  • J Med Chem. 2023 Nov 23;66(22):15269-15287. doi: 10.1021/acs.jmedchem.3c01348.
Linghao Hu 1,  Huiyun Li 1 2,  Junlin Qin 3,  Dan Yang 1 4,  Jieming Liu 1,  Xiaomin Luo 1,  Jingkun Ma,  Cheng Luo 1 3,  Fei Ye 5,  Yubo Zhou 1,  Jia Li 1 2 3,  Mingliang Wang 1 4
Affiliations

Affiliations

  • 1 Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan Tsuihang New District, Guangdong 528400, China.
  • 2 School of Pharmacy, Zunyi Medical University, Zunyi 563000, Guizhou China.
  • 3 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China.
  • 4 School of Pharmaceutical Sciences, Southern Medical University, No.1023, South Shatai Road, Baiyun District, Guangzhou 510515, Guangdong, China.
  • 5 College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou 310018, China.
PMID: 37966047 DOI: 10.1021/acs.jmedchem.3c01348
Abstract

Protein tyrosine Phosphatase nonreceptor Type 2 (PTPN2) is an attractive target for Cancer Immunotherapy. PTPN2 and another subtype of PTP1B are highly similar in structure, but their biological functions are distinct. Therefore, subtype-selective targeting of PTPN2 remains a challenge for researchers. Herein, the development of small molecular PTPN2 degraders based on a thiadiazolidinone dioxide-naphthalene scaffold and a VHL E3 Ligase ligand is described, and the PTPN2/PTP1B subtype-selective degradation is achieved for the first time. The linker structure modifications led to the discovery of the subtype-selective PTPN2 degrader PVD-06 (PTPN2/PTP1B selective index > 60-fold), which also exhibits excellent proteome-wide degradation selectivity. PVD-06 induces PTPN2 degradation in a ubiquitination- and proteasome-dependent manner. It efficiently promotes T cell activation and amplifies IFN-γ-mediated B16F10 cell growth inhibition. This study provides a convenient chemical knockdown tool for PTPN2-related research and a paradigm for subtype-selective PTP degradation through nonspecific substrate-mimicking ligands, demonstrating the therapeutic potential of PTPN2 subtype-selective degradation.

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