Discovery of Potent and Selective Benzothiophene Difluoromethyl Phosphonate (DFMP) PTPN2/N1-Dual Inhibitors.

PTPN1 and PTPN2 are interesting targets for immuno-oncology due to their ability to modulate IFNγ signaling and T-cell activity. We report the discovery of benzothiophene difluoromethyl phosphonate (DFMP) inhibitors with potent dual PTPN1/PTPN2 activity. Structure-based design and a late-stage Ir-catalyzed C-H borylation enabled C5/C7-disubstituted designs that produced a marked inflection in potency. Systematic vector optimization improved potency, selectivity, and pharmacokinetic properties. Mechanistic studies identified SLC19A1 as a key transporter mediating cellular uptake. Lead compound 25 exhibited good potency, high selectivity, favorable PK, and dose-dependent pSTAT1 induction in a MC38 mouse model. These results establish compound 25 as promising structurally differentiated tool to study PTPN1/N2 inhibition and underscore the importance of SLC19A1 in the transport of DFMPs.