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

• Published in: Journal of medicinal chemistry 2023-11, Vol.66 (22), p.15269-15287
• Main Authors: Hu, Linghao, Li, Huiyun, Qin, Junlin, Yang, Dan, Liu, Jieming, Luo, Xiaomin, Ma, Jingkun, Luo, Cheng, Ye, Fei, Zhou, Yubo, Li, Jia, Wang, Mingliang
• Format: Article
• Language: English
• Subjects: Phosphorylation; Proteasome Endopeptidase Complex - metabolism; Protein Tyrosine Phosphatase, Non-Receptor Type 2 - genetics; Protein Tyrosine Phosphatase, Non-Receptor Type 2 - metabolism; Ubiquitin-Protein Ligases - metabolism; Ubiquitination
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.3c01348

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 (PTPN2/PTP1B selective index > 60-fold), which also exhibits excellent proteome-wide degradation selectivity. 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.