8S4F

Human carbonic anhydrase I covalently bound to AV21-08

Summary for 8S4F

• Entry DOI: 10.2210/pdb8s4f/pdb
• Descriptor: Carbonic anhydrase 1, ZINC ION, PROPANOIC ACID, ... (9 entities in total)
• Functional Keywords: drug design, carbonic anhydrase, benzenesulfonamide, metal-binding, lyase-lyase inhibitor complex, lyase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 59302.75

Authors

Manakova, E.N.,Grazulis, S.,Paketuryte-Latve, V.,Vaskevicius, A.,Smirnov, A. (deposition date: 2024-02-21, release date: 2024-12-18, Last modification date: 2025-01-22)

Primary citation

Vaskevicius, A.,Baronas, D.,Leitans, J.,Kvietkauskaite, A.,Ruksenaite, A.,Manakova, E.,Toleikis, Z.,Kaupinis, A.,Kazaks, A.,Gedgaudas, M.,Mickeviciute, A.,Juozapaitiene, V.,Schioth, H.B.,Jaudzems, K.,Valius, M.,Tars, K.,Grazulis, S.,Meyer-Almes, F.J.,Matuliene, J.,Zubriene, A.,Dudutiene, V.,Matulis, D.
Targeted anticancer pre-vinylsulfone covalent inhibitors of carbonic anhydrase IX.
Elife, 13:-, 2024

PubMed Abstract: We designed novel pre-drug compounds that transform into an active form that covalently modifies particular His residue in the active site, a difficult task to achieve, and applied to carbonic anhydrase (CAIX), a transmembrane protein, highly overexpressed in hypoxic solid tumors, important for cancer cell survival and proliferation because it acidifies tumor microenvironment helping invasion and metastases processes. The designed compounds have several functionalities: (1) primary sulfonamide group recognizing carbonic anhydrases (CA), (2) high-affinity moieties specifically recognizing CAIX among all CA isozymes, and (3) forming a covalent bond with the His64 residue. Such targeted covalent compounds possess both high initial affinity and selectivity for the disease target protein followed by complete irreversible inactivation of the protein via covalent modification. Our designed prodrug candidates bearing moderately active pre-vinylsulfone esters or weakly active carbamates optimized for mild covalent modification activity to avoid toxic non-specific modifications and selectively target CAIX. The lead inhibitors reached 2 pM affinity, the highest among known CAIX inhibitors. The strategy could be used for any disease drug target protein bearing a His residue in the vicinity of the active site.

PubMed: 39688904
DOI: 10.7554/eLife.101401

Experimental method

X-RAY DIFFRACTION (1.39 Å)