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

Abstract

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 both in vitro and in 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.

Keywords:

• Carbonic anhydrase IX
• carborane
• enzyme inhibitors
• structure-activity relationship

Disclosure statement

The authors declare the following competing financial interest(s): J. H., J. B., B. G., and P. R. are inventors of a United States Patent, Pat. No. 9,290,529 B2, issued on Mar. 22, 2016, that covers the title compounds.

Additional information

Funding

This work was supported by the Czech Science Foundation [grant number 18-27648S], the Technology Agency of the Czech Republic [grant number TE01020028], European Regional Development Fund [grant number CZ.02.1.01/0.0/0.0/16_019/0000729] and PPLZ of the Czech Academy of Sciences [grant number L200321851 to SEA]. Diffraction data were collected on BL14.1 and BL14.2 at the BESSY II electron storage ring operated by the Helmholtz-Zentrum Berlin.