Characterization of novel dual PTPN1 and PTPN2 inhibitors

Nonreceptor tyrosine phosphatases (NTPs) play an important role regulating protein phosphorylation and have been proposed as attractive therapeutic targets for different diseases. We have previously identified that 3-Hydroxy-1,2,3-benzotriazin-4(3H)-one (HODHBt) enhanced STAT activation upon cytokine treatment. Here, we demonstrated that HODHBt interacts and inhibits the catalytic domain of the NTPs PTPN1 and PTPN2. We confirmed that PTPN1 and PTPN2 specifically control the phosphorylation of STATs. PTPN1 and PTPN2 have been identified as intracellular checkpoint inhibitors that limit immune effector function. We validated that HODHBt enhanced CD8 and γδ-T cells immune effector functions. Finally, we identified a new family of compounds that act as dual PTPN1/PTPN2 inhibitors. Thus, our studies provide a new series of scaffold molecules for the development of specific PTPN1/PTPN2 inhibitors.