9F2N

Structure of human carbonic anhydrase XII complexed with 3-(cyclooctylamino)-2,6-difluoro-4-((3-hydroxypropyl)sulfonyl)-5-(piperidin-1-yl)benzenesulfonamide

This is a non-PDB format compatible entry.

Summary for 9F2N

• Entry DOI: 10.2210/pdb9f2n/pdb
• Related: 9F2O 9F30 9F3G
• Descriptor: Carbonic anhydrase 12, ZINC ION, 1,2-ETHANEDIOL, ... (5 entities in total)
• Functional Keywords: drug design, carbonic anhydrase, benzenesulfonamide, lyase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 61323.11

Authors

Manakova, E.N.,Grazulis, S.,Paketuryte, V.,Smirnov, A. (deposition date: 2024-04-23, release date: 2025-05-14, Last modification date: 2025-09-24)

Primary citation

Vaskevicius, A.,Zvirblis, M.,Kurtenoka, M.,Leitans, J.,Manakova, E.,Paketuryte-Latve, V.,Kvietkauskaite, A.,Kazaks, A.,Eimonta, V.,Cerepenkaite, K.,Kazokaite-Adomaitiene, J.,Mickeviciu̅te, A.,Juozapaitiene, V.,Tars, K.,Grazulis, S.,Matuliene, J.,Dudutiene, V.,Shubin, K.,Matulis, D.,Zubriene, A.
Di- meta -Substituted Fluorinated Benzenesulfonamides as Potent and Selective Anticancer Inhibitors of Carbonic Anhydrase IX and XII.
J.Med.Chem., 68:18389-18406, 2025

PubMed Abstract: The development of selective drug candidate molecules for cancer-related carbonic anhydrase isozymes IX and XII is challenging due to high homology binding sites among 12 catalytically active isozymes. Starting from the trifluorinated benzenesulfonamide with cyclooctylamino substituent at the position, we designed and synthesized di--substituted fluorinated benzenesulfonamides with up to 10-fold affinity improvement for CAIX, resulting in low picomolar binders. The resulting CAIX-targeting compounds showed up to 1000-fold selectivity over off-target CA isozymes. The crystal structures of CAIX and CAXII complexes with synthesized compounds revealed detailed insights into protein-ligand interactions and adopted complex conformation. The potential of compounds with reduced off-target effects as possible anticancer drugs is supported by this study.

PubMed: 40833423
DOI: 10.1021/acs.jmedchem.5c01142

Experimental method

X-RAY DIFFRACTION (1.21 Å)