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 canc...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications Ltd
2024-12-01
|
| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/101401 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850249610563420160 |
|---|---|
| author | Aivaras Vaškevičius Denis Baronas Janis Leitans Agnė Kvietkauskaitė Audronė Rukšėnaitė Elena Manakova Zigmantas Toleikis Algirdas Kaupinis Andris Kazaks Marius Gedgaudas Aurelija Mickevičiūtė Vaida Juozapaitienė Helgi B Schiöth Kristaps Jaudzems Mindaugas Valius Kaspars Tars Saulius Gražulis Franz-Josef Meyer-Almes Jurgita Matulienė Asta Zubrienė Virginija Dudutienė Daumantas Matulis |
| author_facet | Aivaras Vaškevičius Denis Baronas Janis Leitans Agnė Kvietkauskaitė Audronė Rukšėnaitė Elena Manakova Zigmantas Toleikis Algirdas Kaupinis Andris Kazaks Marius Gedgaudas Aurelija Mickevičiūtė Vaida Juozapaitienė Helgi B Schiöth Kristaps Jaudzems Mindaugas Valius Kaspars Tars Saulius Gražulis Franz-Josef Meyer-Almes Jurgita Matulienė Asta Zubrienė Virginija Dudutienė Daumantas Matulis |
| author_sort | Aivaras Vaškevičius |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-d2000c0aa6154247b81fece6681bfd67 |
| institution | OA Journals |
| issn | 2050-084X |
| language | English |
| publishDate | 2024-12-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj-art-d2000c0aa6154247b81fece6681bfd672025-08-20T01:58:28ZengeLife Sciences Publications LtdeLife2050-084X2024-12-011310.7554/eLife.101401Targeted anticancer pre-vinylsulfone covalent inhibitors of carbonic anhydrase IXAivaras Vaškevičius0https://orcid.org/0009-0006-8202-9748Denis Baronas1https://orcid.org/0000-0003-1878-0837Janis Leitans2Agnė Kvietkauskaitė3Audronė Rukšėnaitė4Elena Manakova5Zigmantas Toleikis6Algirdas Kaupinis7Andris Kazaks8Marius Gedgaudas9Aurelija Mickevičiūtė10Vaida Juozapaitienė11Helgi B Schiöth12Kristaps Jaudzems13Mindaugas Valius14Kaspars Tars15Saulius Gražulis16Franz-Josef Meyer-Almes17https://orcid.org/0000-0002-1001-3249Jurgita Matulienė18Asta Zubrienė19Virginija Dudutienė20Daumantas Matulis21https://orcid.org/0000-0002-6178-6276Department of Biothermodynamics and Drug Design, Institute of Biotechnology, Life Sciences Center, Vilnius University, Vilnius, LithuaniaDepartment of Biothermodynamics and Drug Design, Institute of Biotechnology, Life Sciences Center, Vilnius University, Vilnius, LithuaniaLatvian Biomedical Research and Study Centre, Riga, LatviaDepartment of Biothermodynamics and Drug Design, Institute of Biotechnology, Life Sciences Center, Vilnius University, Vilnius, LithuaniaDepartment of Biological DNA Modification, Institute of Biotechnology, Life Sciences Center, Vilnius University, Vilnius, LithuaniaDepartment of Protein - DNA Interactions, Institute of Biotechnology, Life Sciences Center, Vilnius University, Vilnius, LithuaniaSector of Biocatalysis, Institute of Biotechnology, Life Sciences Center, Vilnius University, Vilnius, LithuaniaProteomics Center, Institute of Biochemistry, Life Sciences Center, Vilnius University, Vilnius, LithuaniaLatvian Biomedical Research and Study Centre, Riga, LatviaDepartment of Biothermodynamics and Drug Design, Institute of Biotechnology, Life Sciences Center, Vilnius University, Vilnius, LithuaniaDepartment of Biothermodynamics and Drug Design, Institute of Biotechnology, Life Sciences Center, Vilnius University, Vilnius, LithuaniaDepartment of Biothermodynamics and Drug Design, Institute of Biotechnology, Life Sciences Center, Vilnius University, Vilnius, LithuaniaFunctional Pharmacology and Neuroscience, Department of Surgical Sciences, Uppsala University, Uppsala, SwedenLatvian Institute of Organic Synthesis, Riga, LatviaProteomics Center, Institute of Biochemistry, Life Sciences Center, Vilnius University, Vilnius, LithuaniaLatvian Biomedical Research and Study Centre, Riga, LatviaSector of Crystallography and Chemical Informatics, Institute of Biotechnology, Life Sciences Center, Vilnius University, Vilnius, LithuaniaDepartment of Chemical Engineering and Biotechnology, University of Applied Sciences Darmstadt, Darmstadt, GermanyDepartment of Biothermodynamics and Drug Design, Institute of Biotechnology, Life Sciences Center, Vilnius University, Vilnius, LithuaniaDepartment of Biothermodynamics and Drug Design, Institute of Biotechnology, Life Sciences Center, Vilnius University, Vilnius, LithuaniaDepartment of Biothermodynamics and Drug Design, Institute of Biotechnology, Life Sciences Center, Vilnius University, Vilnius, LithuaniaDepartment of Biothermodynamics and Drug Design, Institute of Biotechnology, Life Sciences Center, Vilnius University, Vilnius, LithuaniaWe 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.https://elifesciences.org/articles/101401targeted covalent inhibitorscarbonic anhydrase IXvinylsulfonesulfonamidefluorescent thermal shift assayX-ray crystallography |
| spellingShingle | Aivaras Vaškevičius Denis Baronas Janis Leitans Agnė Kvietkauskaitė Audronė Rukšėnaitė Elena Manakova Zigmantas Toleikis Algirdas Kaupinis Andris Kazaks Marius Gedgaudas Aurelija Mickevičiūtė Vaida Juozapaitienė Helgi B Schiöth Kristaps Jaudzems Mindaugas Valius Kaspars Tars Saulius Gražulis Franz-Josef Meyer-Almes Jurgita Matulienė Asta Zubrienė Virginija Dudutienė Daumantas Matulis Targeted anticancer pre-vinylsulfone covalent inhibitors of carbonic anhydrase IX eLife targeted covalent inhibitors carbonic anhydrase IX vinylsulfone sulfonamide fluorescent thermal shift assay X-ray crystallography |
| title | Targeted anticancer pre-vinylsulfone covalent inhibitors of carbonic anhydrase IX |
| title_full | Targeted anticancer pre-vinylsulfone covalent inhibitors of carbonic anhydrase IX |
| title_fullStr | Targeted anticancer pre-vinylsulfone covalent inhibitors of carbonic anhydrase IX |
| title_full_unstemmed | Targeted anticancer pre-vinylsulfone covalent inhibitors of carbonic anhydrase IX |
| title_short | Targeted anticancer pre-vinylsulfone covalent inhibitors of carbonic anhydrase IX |
| title_sort | targeted anticancer pre vinylsulfone covalent inhibitors of carbonic anhydrase ix |
| topic | targeted covalent inhibitors carbonic anhydrase IX vinylsulfone sulfonamide fluorescent thermal shift assay X-ray crystallography |
| url | https://elifesciences.org/articles/101401 |
| work_keys_str_mv | AT aivarasvaskevicius targetedanticancerprevinylsulfonecovalentinhibitorsofcarbonicanhydraseix AT denisbaronas targetedanticancerprevinylsulfonecovalentinhibitorsofcarbonicanhydraseix AT janisleitans targetedanticancerprevinylsulfonecovalentinhibitorsofcarbonicanhydraseix AT agnekvietkauskaite targetedanticancerprevinylsulfonecovalentinhibitorsofcarbonicanhydraseix AT audroneruksenaite targetedanticancerprevinylsulfonecovalentinhibitorsofcarbonicanhydraseix AT elenamanakova targetedanticancerprevinylsulfonecovalentinhibitorsofcarbonicanhydraseix AT zigmantastoleikis targetedanticancerprevinylsulfonecovalentinhibitorsofcarbonicanhydraseix AT algirdaskaupinis targetedanticancerprevinylsulfonecovalentinhibitorsofcarbonicanhydraseix AT andriskazaks targetedanticancerprevinylsulfonecovalentinhibitorsofcarbonicanhydraseix AT mariusgedgaudas targetedanticancerprevinylsulfonecovalentinhibitorsofcarbonicanhydraseix AT aurelijamickeviciute targetedanticancerprevinylsulfonecovalentinhibitorsofcarbonicanhydraseix AT vaidajuozapaitiene targetedanticancerprevinylsulfonecovalentinhibitorsofcarbonicanhydraseix AT helgibschioth targetedanticancerprevinylsulfonecovalentinhibitorsofcarbonicanhydraseix AT kristapsjaudzems targetedanticancerprevinylsulfonecovalentinhibitorsofcarbonicanhydraseix AT mindaugasvalius targetedanticancerprevinylsulfonecovalentinhibitorsofcarbonicanhydraseix AT kasparstars targetedanticancerprevinylsulfonecovalentinhibitorsofcarbonicanhydraseix AT sauliusgrazulis targetedanticancerprevinylsulfonecovalentinhibitorsofcarbonicanhydraseix AT franzjosefmeyeralmes targetedanticancerprevinylsulfonecovalentinhibitorsofcarbonicanhydraseix AT jurgitamatuliene targetedanticancerprevinylsulfonecovalentinhibitorsofcarbonicanhydraseix AT astazubriene targetedanticancerprevinylsulfonecovalentinhibitorsofcarbonicanhydraseix AT virginijadudutiene targetedanticancerprevinylsulfonecovalentinhibitorsofcarbonicanhydraseix AT daumantasmatulis targetedanticancerprevinylsulfonecovalentinhibitorsofcarbonicanhydraseix |