Chemical Modulation of the cGAS‐STING‐ENPP1 Axis: Medicinal Chemistry and Clinical Perspective

The cyclic GMP‐AMP synthase (cGAS)‐stimulator of interferon genes (STING) pathway plays a fundamental role in innate immune signaling and has emerged as a therapeutically relevant pathway across cancer, inflammatory, and autoimmune diseases. Herein, we provide a comprehensive medicinal chemistry‐focused overview of both activation and inhibition of the cGAS‐STING pathway, focusing on three druggable therapeutic targets, cGAS, STING, and ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1). The translational maturity of these targets differs substantially, with STING being the most clinically advanced, whereas cGAS and ENPP1 remain emerging targets supported predominantly by preclinical evidence, with the advancement of a few inhibitors into early‐stage clinical trials. The biological rationale for pathway modulation, along with modulators, is discussed with emphasis on active site interactions, scaffold diversity, their activity profiles, structure–activity relationships, species selectivity, and in vivo efficacy. The particular focus is on patent literature and advanced‐stage molecules, discussing their ADME properties, pharmacokinetics, and clinical development status. Although STING agonists have achieved a larger reach in clinical trials within this pathway, recent developments suggest that cGAS inhibitors and ENPP1 inhibitors hold a greater promise for future clinical success. In summary, this review provides insights into medicinal chemistry and translational challenges and future opportunities for rational drug design to guide next‐generation modulators of the cGAS‐STING‐ENPP1 axis.