Inhibition of Ectonucleotide Pyrophosphatase/Phosphodiesterase 1 (ENPP1): A Medicinal Chemistry Approach at the Crossroad of Immunotherapy and Metabolic Modulation

The ectonucleotide pyrophosphatase/phosphodiesterase (ENPP) family regulates critical processes, including nucleotide signaling, bone mineralization, and tumor immune infiltration. Consequently, ENPP1 is recently being re-discovered as a novel target for immunotherapy in cancer and other diseases. ENPP1 hydrolyzes extracellular nucleotides, modulating calcification and immune responses, and mounting evidence shows that its inhibition through small molecules, including natural compounds, enhances antitumor immunity and metabolic modulation. In this mini-review, we overview medicinal chemistry strategies, including structure-based design and nature-inspired molecules, leading to promising candidates inhibiting ENPP1 with demonstrated preclinical efficacy, alone or in combination therapies. The potential of ENPP1 as a druggable target is explored through a survey of over 70 recent scientific articles. While ENPP1 represents an attractive target in several diseases, limitations are still present: preclinical progresses, challenges in selectivity, and future directions for optimizing lead compounds are discussed within the mini-review.