2. Academic Validation
  3. Targeted anticancer pre-vinylsulfone covalent inhibitors of carbonic anhydrase IX

Targeted anticancer pre-vinylsulfone covalent inhibitors of carbonic anhydrase IX

  • Elife. 2024 Dec 17:13:RP101401. doi: 10.7554/eLife.101401.
Aivaras Vaškevičius 1,  Denis Baronas 1,  Janis Leitans 2,  Agnė Kvietkauskaitė 1,  Audronė Rukšėnaitė 3,  Elena Manakova 4,  Zigmantas Toleikis 5,  Algirdas Kaupinis 6,  Andris Kazaks 2,  Marius Gedgaudas 1,  Aurelija Mickevičiūtė 1,  Vaida Juozapaitienė 1,  Helgi B Schiöth 7,  Kristaps Jaudzems 8,  Mindaugas Valius 6,  Kaspars Tars 2,  Saulius Gražulis 9,  Franz-Josef Meyer-Almes 10,  Jurgita Matulienė 1,  Asta Zubrienė 1,  Virginija Dudutienė 1,  Daumantas Matulis 1
Affiliations

Affiliations

  • 1 Department of Biothermodynamics and Drug Design, Institute of Biotechnology, Life Sciences Center, Vilnius University, Vilnius, Lithuania.
  • 2 Latvian Biomedical Research and Study Centre, Riga, Latvia.
  • 3 Department of Biological DNA Modification, Institute of Biotechnology, Life Sciences Center, Vilnius University, Vilnius, Lithuania.
  • 4 Department of Protein - DNA Interactions, Institute of Biotechnology, Life Sciences Center, Vilnius University, Vilnius, Lithuania.
  • 5 Sector of Biocatalysis, Institute of Biotechnology, Life Sciences Center, Vilnius University, Vilnius, Lithuania.
  • 6 Proteomics Center, Institute of Biochemistry, Life Sciences Center, Vilnius University, Vilnius, Lithuania.
  • 7 Functional Pharmacology and Neuroscience, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
  • 8 Latvian Institute of Organic Synthesis, Riga, Latvia.
  • 9 Sector of Crystallography and Chemical Informatics, Institute of Biotechnology, Life Sciences Center, Vilnius University, Vilnius, Lithuania.
  • 10 Department of Chemical Engineering and Biotechnology, University of Applied Sciences Darmstadt, Darmstadt, Germany.
PMID: 39688904 DOI: 10.7554/eLife.101401
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.

Keywords

X-ray crystallography; carbonic anhydrase IX; fluorescent thermal shift assay; molecular biophysics; none; structural biology; sulfonamide; targeted covalent inhibitors; vinylsulfone.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z