By hydrolysing 2',3'-cyclic GMP-AMP dinucleotide (2',3'-cGAMP), ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) regulates downstream pathways related to cancer progression and immunomodulation. Thus, it represents an attractive target for the discovery of novel ligands. We here disclose the activity of Dinaphthodiospyrol F and dinaphthodiospyrol G, two dimeric naphthoquinones extracted from Diospyros lotus L. as ENPP1 inhibitors by means of computational and in vitro techniques. Our study showed that the two molecules inhibit ENPP1 with a potency similar to that of the positive control (disodium EDTA), suggesting their possible use as new natural scaffolds in the development of optimised derivatives.
Rauf et al. (2026) studied this question.