化学
蛋白酶体
泛素
泛素连接酶
蛋白质酪氨酸磷酸酶
蛋白质降解
小分子
计算生物学
癌症研究
生物化学
酪氨酸
生物
基因
作者
Linghao Hu,Kun Xu,Junlin Qin,Dan Yang,Jieming Liu,Xiaomin Luo,Jingkun Ma,Cheng Luo,Fei Ye,Yubo Zhou,Jia Li,Mingliang Wang
标识
DOI:10.1021/acs.jmedchem.3c01348
摘要
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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