Dual-target carbonic anhydrase inhibitors in cancer therapy: progress, challenges, and opportunities.

Carbonic anhydrases (CA) are metalloenzymes that mediate diverse physiological and pathological processes, including pH, metabolism, and electrolyte balance, making them key therapeutic targets. Although numerous carbonic anhydrase inhibitors are clinically used for glaucoma, mountain sickness, hypoxic tumors and epilepsy, their efficacy is often limited by systemic toxicity, drug resistance, and poor activity against multifactorial diseases. Multi-target combination therapy, particularly via dual-target agents, offers a promising strategy to overcome these hurdles. Given the synergistic relationships between CA and epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor (VEGFR) and histone deacetylase (HDAC), among other common drug targets, dual-target carbonic anhydrase inhibitors (CAIs) hold great potential to circumvent current limitations and enhance treatment outcomes. This review summarizes recent progress in dual-target CAIs, emphasizing design strategies, structure-activity relationships (SAR), and translational challenges, and provides a theoretical foundation and innovative perspectives for next-generation CA-directed therapies.