Achieving femtomolar affinities in structure-based drug design.

Developing small-molecule compounds as effective and safe pharmaceuticals relies on their ability to bind disease-associated proteins with high affinity and selectivity. However, achieving ultra-high affinity in the femtomolar range is a major challenge in medicinal chemistry due to the inherent constraints of protein-ligand interactions. Here, we introduce a novel class of di-meta-substituted fluorinated benzenesulfonamide compounds that achieve an extraordinary dissociation constant of 44 fM for carbonic anhydrase IX (CAIX). CAIX, a transmembrane enzyme implicated in hypoxic tumor progression through the increase of microenvironment acidity, represents a promising target for anticancer therapy. Inhibiting CAIX may help suppress tumor growth and improve cancer treatment outcomes. The newly developed compounds exhibit the highest affinity for CAIX reported to date and rank among the strongest known non-covalent small-molecule inhibitors.