DPP9-IN-2 is a selective and potent orally active inhibitor of dipeptidyl peptidase 9 (DPP9), with an IC50 value of 12.9 nM. It exhibits a selectivity index of 59 for DPP8 and shows no significant inhibitory activity on related peptidases, including DPP2, DPP4, FAP, and PREP. DPP9-IN-2 can induce pyroptosis in cancer cells and demonstrates modest synergistic anti-HIV-1 activity when combined with non-nucleoside reverse transcriptase inhibitors. This compound is applicable for research in cancer and infection.

DPP9:12.9 nM

DPP9-IN-2 (Compound 6e) at concentrations of 0.05-5 μM and exposure times between 24-48 hours induces pyroptosis in THP-1 cells, leading to increased LDH release and SYTOX Green uptake. When used at 0.5-5 μM for 24 hours, DPP9-IN-2-induced pyroptosis relies on DPP9, CASP1, and GSDMD, and is significantly inhibited or delayed in THP-1 cells that have DPP9 knockdown, CASP1 knockout, or GSDMD knockout. At 5 μM, DPP9-IN-2 shows weak synergistic anti-HIV-1 activity in combination with non-nucleoside reverse transcriptase inhibitors, such as Efavirenz and Rilpivirine, in MT-4 cells.

DPP9-IN-2 (Compound 6e) either intravenously at 5 mg/kg or orally at 20 mg/kg increases the necrosis rate of CD3⁻CD11b⁻ leukocytes (such as B cells and NK cells) in Wistar rats.