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.

人碳酸酐酶IX（CA IX）是一种在实体瘤细胞表面上特异性表达的蛋白质，是经过验证的抗癌和诊断靶标。最近，我们确定了磺胺二甲碳硼烷是有希望的CA IX抑制剂，在体内和体外均具有良好的活性。。为了解释它们的选择性和效力，我们对CA IX和CA II的活性位点之间的相互作用进行了详细的X射线结构分析。考察了在双碳硼烷簇和磺酰胺基团之间带有各种脂族连接基的一系列化合物。观察到与活性位点腔的疏水部分的优先结合。对CA IX的选择性在于双碳硼烷簇与包含V131残基的特定CA IX疏水贴剂的形状互补性。CA II中F131残基的庞大侧链会改变催化腔的形状，从而破坏球形双碳六硼烷簇的良好相互作用。