Discovery of PVD-06 as a Subtype-Selective and Efficient PTPN2 Degrader,Journal of Medicinal Chemistry

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Discovery of PVD-06 as a Subtype-Selective and Efficient PTPN2 Degrader
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2023-11-15 , 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}

Affiliation

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.

中文翻译：

发现 PVD-06 作为亚型选择性高效 PTPN2 降解剂

2 型蛋白酪氨酸磷酸酶非受体 (PTPN2) 是癌症免疫治疗的一个有吸引力的靶点。 PTPN2与PTP1B的另一个亚型在结构上高度相似，但其生物学功能却截然不同。因此，PTPN2的亚型选择性靶向仍然是研究人员面临的挑战。在此，描述了基于二氧化噻二唑烷酮-萘支架和VHL E3连接酶配体的小分子PTPN2降解剂的开发，并首次实现了PTPN2/PTP1B亚型选择性降解。连接子结构的修饰导致亚型选择性 PTPN2 降解剂PVD-06的发现（PTPN2/PTP1B 选择性指数 > 60 倍），它还表现出优异的全蛋白质组降解选择性。 PVD-06以泛素化和蛋白酶体依赖性方式诱导 PTPN2 降解。它有效促进 T 细胞活化并放大 IFN-γ 介导的 B16F10 细胞生长抑制。这项研究为PTPN2相关研究提供了一种方便的化学敲低工具，并为通过非特异性底物模拟配体进行亚型选择性PTP降解提供了范例，证明了PTPN2亚型选择性降解的治疗潜力。

更新日期：2023-11-15

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