The structural basis for the selectivity of sulfonamido dicarbaboranes toward cancer-associated carbonic anhydrase IX

0539170 - ÚMG 2021 RIV GB eng J - Journal Article
Kugler, Michael - Holub, J. - Brynda, Jiří - Pospíšilová, K. - El Anwar, S. - Bavol, D. - Havránek, M. - Král, Vlastimil - Fábry, Milan - Gruner, B. - Řezáčová, Pavlína
The structural basis for the selectivity of sulfonamido dicarbaboranes toward cancer-associated carbonic anhydrase IX.
Journal of Enzyme Inhibition and Medicinal Chemistry. Roč. 35, č. 1 (2020), s. 1800-1810. ISSN 1475-6366. E-ISSN 1475-6374
Institutional support: RVO:68378050
Keywords : tumor hypoxia * medicinal chemistry * drug discovery * binding-sites * inhibition * boron * pharmacophores * opportunities * conjugation * metastasis * Carbonic anhydrase IX * carborane * enzyme inhibitors * structure-activity relationship
OECD category: Biochemistry and molecular biology
Impact factor: 5.051, year: 2020
Method of publishing: Open access
https://www.tandfonline.com/doi/full/10.1080/14756366.2020.1816996

Human carbonic anhydrase IX (CA IX), a protein specifically expressed on the surface of solid tumour cells, represents a validated target both for anticancer therapy and diagnostics. We recently identified sulfonamide dicarbaboranes as promising inhibitors of CA IX with favourable activities bothin vitroandin vivo. To explain their selectivity and potency, we performed detailed X-ray structural analysis of their interactions within the active sites of CA IX and CA II. Series of compounds bearing various aliphatic linkers between the dicarbaborane cluster and sulfonamide group were examined. Preferential binding towards the hydrophobic part of the active site cavity was observed. Selectivity towards CA IX lies in the shape complementarity of the dicarbaborane cluster with a specific CA IX hydrophobic patch containing V131 residue. The bulky side chain of F131 residue in CA II alters the shape of the catalytic cavity, disrupting favourable interactions of the spherical dicarbaborane cluster.
Permanent Link: http://hdl.handle.net/11104/0316870