ENPP1 inhibitor 4e is an inhibitor of ectonucleotide pyrophosphatase/phosphodiesterase family member 1 (ENPP1; IC50 = 0.188 µM), an enzyme that degrades the stimulator of interferon genes (STING) activator 2'3'-cGAMP .1 It inhibits ENPP1 in MDA-MB-231 cells, which highly express ENPP1 (IC50 = 0.732 µM). ENPP1 inhibitor 4e is selectively cytotoxic to 4T1 murine metastatic breast cancer cells (IC50 = 2.99 µM) over non-cancerous L-02 and 293T cells at 50 µM. It increases serum levels of IFN-β in mice when administered at a dose of 0.5 mg/kg in combination with cGAMP when compared to mice administered only cGAMP or mice not receiving either compound, indicating that ENPP1 inhibitor 4e reduces the degradation of cGAMP.
1.Wang, X., Lu, X., Yan, D., et al.Development of novel ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) inhibitors for tumor immunotherapyInt. J. Mol. Sci.23(13)7104(2022)