PDBsum entry 6t7u

Lyase

PDB id: 6t7u

Contents

Protein chain

257 a.a.

Ligands

X33

Metals

_ZN

Waters ×287

PDB id:

6t7u

Name:

Lyase

Title:

Carborane inhibitor of carbonic anhydrase ix

Structure:

Carbonic anhydrase 2. Chain: a. Synonym: carbonate dehydratase ii,carbonic anhydrasE C,cac,carbonic anhydrase ii,ca-ii. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: ca2. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

1.20Å R-factor: 0.138 R-free: 0.160

Authors:

J.Brynda,P.Rezacova,M.Kugler,B.Gruner

Key ref:

J.Dvořanová et al. (2020). Sulfonamido carboranes as highly selective inhibitors of cancer-specific carbonic anhydrase IX. Eur J Med Chem, 200, 112460. PubMed id: 32505851 DOI: 10.1016/j.ejmech.2020.112460

Date:

23-Oct-19 Release date: 17-Jun-20

Protein chain

P00918  (CAH2_HUMAN) -  Carbonic anhydrase 2 from Homo sapiens

Seq: 260 a.a.

Struc: 257 a.a.*

* PDB and UniProt seqs differ at 7 residue positions (black crosses)

Enzyme reactions

• Enzyme class 2: E.C.4.2.1.1 - carbonic anhydrase.
• Reaction: hydrogencarbonate + H⁺ = CO2 + H2O
• Cofactor: Zn(2+)
• Enzyme class 3: E.C.4.2.1.69 - cyanamide hydratase.
• Reaction: urea = cyanamide + H2O

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1016/j.ejmech.2020.112460

Eur J Med Chem 200:112460 (2020)

PubMed id: 32505851

Sulfonamido carboranes as highly selective inhibitors of cancer-specific carbonic anhydrase IX.

J.Dvořanová, M.Kugler, J.Holub, V.Šícha, V.Das, J.Nekvinda, S.El Anwar, M.Havránek, K.Pospíšilová, M.Fábry, V.Král, M.Medvedíková, S.Matějková, B.Lišková, S.Gurská, P.Džubák, J.Brynda, M.Hajdúch, B.Grüner, P.Řezáčová.

ABSTRACT

Carbonic anhydrase IX (CA IX) is a transmembrane enzyme overexpressed in hypoxic tumors, where it plays an important role in tumor progression. Specific CA IX inhibitors potentially could serve as anti-cancer drugs. We designed a series of sulfonamide inhibitors containing carborane clusters based on prior structural knowledge of carborane binding into the enzyme active site. Two types of carborane clusters, 12-vertex dicarba-closo-dodecaborane and 11-vertex 7,8-dicarba-nido-undecaborate (dicarbollide), were connected to a sulfonamide moiety via aliphatic linkers of varying lengths (1-4 carbon atoms; n = 1-4). In vitro testing of CA inhibitory potencies revealed that the optimal linker length for selective inhibition of CA IX was n = 3. A 1-sulfamidopropyl-1,2-dicarba-closo-dodecaborane (3) emerged as the strongest CA IX inhibitor from this series, with a K_i value of 0.5 nM and roughly 1230-fold selectivity towards CA IX over CA II. X-ray studies of 3 yielded structural insights into their binding modes within the CA IX active site. Compound 3 exhibited moderate cytotoxicity against cancer cell lines and primary cell lines in 2D cultures. Cytotoxicity towards multicellular spheroids was also observed. Moreover, 3 significantly lowered the amount of CA IX on the cell surface both in 2D cultures and spheroids and facilitated penetration of doxorubicin. Although 3 had only a moderate effect on tumor size in mice, we observed favorable ADME properties and pharmacokinetics in mice, and preferential presence in brain over serum.