Structural Basis of Saccharin Derivative Inhibition of Carbonic Anhydrase IX

Leitans, Janis; Kazaks, Andris; Bogans, Janis; Supuran, Claudiu T.; Akopjana, Inara; Ivanova, Jekaterina; Zalubovskis, Raivis; Tars, Kaspars

doi:10.1002/cmdc.202300454

Targeted anticancer pre-vinylsulfone covalent inhibitors of carbonic anhydrase IX

Vaškevičius,

Baronas,

Leitans

et al. 2024

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The CA IX is 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. We designed novel compounds that have several functionalities: 1) primary sulfonamide group recognizing carbonic anhydrases (CA), 2) high-affinity moieties specifically recognizing CA IX among all CA isozymes, and 3) forming a covalent bond with the His64 residue. Such targeted covalent compounds possess both high 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-vinyl sulfone esters or weakly active carbamates optimized for mild covalent modification activity to avoid toxic non-specific modifications and selectively target CA IX. The lead inhibitors reached 2 pM affinity, highest among known CA IX inhibitors. The strategy could be used for any disease drug target protein bearing a His residue in the vicinity of the active site.

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Targeted anticancer pre-vinylsulfone covalent inhibitors of carbonic anhydrase IX

Vaškevičius,

Baronas,

Leitans

et al. 2024

eLife

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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-vinyl sulfone 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, 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.

show abstract

Targeted anticancer pre-vinylsulfone covalent inhibitors of carbonic anhydrase IX

Vaškevičius,

Baronas,

Leitans

et al. 2024

Preprint

0

View full text Add to dashboard Cite

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-vinyl sulfone 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, 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.

show abstract

Structural Basis of Saccharin Derivative Inhibition of Carbonic Anhydrase IX

Cited by 5 publications

References 24 publications

Targeted anticancer pre-vinylsulfone covalent inhibitors of carbonic anhydrase IX

Targeted anticancer pre-vinylsulfone covalent inhibitors of carbonic anhydrase IX

Targeted anticancer pre-vinylsulfone covalent inhibitors of carbonic anhydrase IX

Targeted anticancer pre-vinylsulfone covalent inhibitors of carbonic anhydrase IX

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