Targeted anticancer pre-vinylsulfone covalent inhibitors of carbonic anhydrase IX
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.
Authors
- Agnė Kvietkauskaitė
- Audronė Rukšėnaitė (ORCID: https://orcid.org/0000-0003-2744-486X)
- Asta Zubrienė (ORCID: https://orcid.org/0000-0001-5996-1883)
- Jurgita Matulienė (ORCID: https://orcid.org/0009-0001-1672-4519)
- Denis Baronas (ORCID: https://orcid.org/0000-0003-1878-0837)
- Aurelija Mickevičiu̅tė (ORCID: https://orcid.org/0000-0003-1717-7112)
- Marius Gedgaudas (ORCID: https://orcid.org/0000-0002-8898-8492)
- Aivaras Vaškevičius (ORCID: https://orcid.org/0009-0006-8202-9748)
- Mindaugas Valius (ORCID: https://orcid.org/0000-0001-8478-8517)
- Algirdas Kaupinis (ORCID: https://orcid.org/0000-0003-3157-6670)
- Zigmantas Toleikis (ORCID: https://orcid.org/0000-0003-1292-8095)
- Franz‐Josef Meyer‐Almes (ORCID: https://orcid.org/0000-0002-1001-3249)
- Virginija Dudutienė (ORCID: https://orcid.org/0000-0002-2864-7143)
- S. Gražulis (ORCID: https://orcid.org/0000-0002-7928-5218)
- E. Manakova (ORCID: https://orcid.org/0000-0002-6027-2265)
- Daumantas Matulis (ORCID: https://orcid.org/0000-0002-6178-6276)
- Ja̅nis Leita̅ns (ORCID: https://orcid.org/0000-0002-4853-8147)
- Andris Kazāks (ORCID: https://orcid.org/0000-0003-4964-0984)
- Vaida Juozapaitienė
- Kristaps Jaudzems (ORCID: https://orcid.org/0000-0003-3922-2447)
- Helgi B. Schiöth (ORCID: https://orcid.org/0000-0001-7112-0921)
- Kaspars Tars
Institutions
- Uppsala University (SE)
- Latvian Biomedical Research and Study Centre (LV)
- Vilnius University (LT)
- Technische Universität Darmstadt (DE)
- Czech Academy of Sciences, Institute of Biotechnology (CZ)
- Latvijas Organiskās Sintēzes Institūts (LV)
- Institute of Organic Synthesis (RU)
Publication Details
- Journal
- eLife
- Published
- 2024-09-26
- DOI
- https://doi.org/10.7554/elife.101401
- Citations
- 4
- Primary Topic
- Enzyme function and inhibition
- Type
- article
- Field-Weighted Citation Impact
- 0.94
Funders
- European Commission
- Lietuvos Mokslo Taryba
- Deutsches Elektronen-Synchrotron