9RBL

Three dimensional structure of human carbonic anhydrase IX in complex with sulfonamide MKV558

This is a non-PDB format compatible entry.

Summary for 9RBL

• Entry DOI: 10.2210/pdb9rbl/pdb
• Descriptor: Carbonic anhydrase 9, ZINC ION, 3-(Cyclooctylamino)-5-ethoxy-2,6-difluoro-4-((3-hydroxypropyl)sulfonyl)benzenesulfonamide, ... (4 entities in total)
• Functional Keywords: ca ix, ca 9, carbonic anhydrase ix, carbonic anhydrase 9, lyase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 4
• Total formula weight: 114558.34

Authors

Leitans, J.,Tars, K. (deposition date: 2025-05-27, release date: 2026-05-27)

Primary citation

Zubriene, A.,Kurtenoka, M.,Paketuryte-Latve, V.,Leitans, J.,Manakova, E.,Zvirblis, M.,Kazaks, A.,Eimonta, V.,Tars, K.,Grazulis, S.,Petrauskas, V.,Matuliene, J.,Dudutiene, V.,Shubin, K.,Matulis, D.
Achieving femtomolar affinities in structure-based drug design.
Eur.Biophys.J., 55:55-62, 2026

PubMed Abstract: 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.

PubMed: 41553426
DOI: 10.1007/s00249-025-01812-5

Experimental method

X-RAY DIFFRACTION (2.05 Å)