Delving into the Latest Updates on PVD-06 with Synapse

Overview

Basic Info

Drug Type

Proteolysis-targeting chimeras (PROTAC)

Synonyms

Target

PTPN2

Mechanism

PTPN2 inhibitors(Tyrosine-protein phosphatase non-receptor type 2 inhibitors)

Therapeutic Areas

Neoplasms

Active Indication

Neoplasms

Inactive Indication-

Originator Organization

Zhongshan Institute for Drug Discovery

Active Organization

Zhongshan Institute for Drug Discovery

Inactive Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

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.

100 Deals associated with PVD-06

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