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PDBsum entry 6t7u
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References listed in PDB file
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Key reference
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Title
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Sulfonamido carboranes as highly selective inhibitors of cancer-Specific carbonic anhydrase IX.
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Authors
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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.
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Ref.
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Eur J Med Chem, 2020,
200,
112460.
[DOI no: ]
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PubMed id
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Abstract
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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 Ki 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.
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