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.

• Klíčová slova
• Carbonic anhydrase IX, carborane, enzyme inhibitors, structure-activity relationship,
• MeSH
• antigeny nádorové genetika   MeSH
• HEK293 buňky MeSH
• hydrofobní a hydrofilní interakce MeSH
• inhibitory karboanhydras chemie   farmakologie   MeSH
• karboanhydrasa IX antagonisté a inhibitory   genetika   MeSH
• katalytická doména MeSH
• krystalografie rentgenová MeSH
• lidé MeSH
• protinádorové látky chemie   farmakologie   MeSH
• screeningové testy protinádorových léčiv MeSH
• sekvence aminokyselin MeSH
• sloučeniny boru chemie   MeSH
• sulfonamidy chemie   farmakologie   MeSH
• vazba proteinů MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antigeny nádorové MeSH
• CA9 protein, human MeSH Prohlížeč
• decaborane MeSH Prohlížeč
• inhibitory karboanhydras MeSH
• karboanhydrasa IX MeSH
• protinádorové látky MeSH
• sloučeniny boru MeSH
• sulfonamidy MeSH