Structural Insights into Carbonic Anhydrase IX Isoform Specificity of Carbohydrate-Based Sulfamates

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• 作者：Janina Moeker ; Brian P. Mahon ; Laurent F. Bornaghi ; Daniela Vullo ; Claudiu T. Supuran ; Robert McKenna ; Sally-Ann Poulsen
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：October 23, 2014
• 年：2014
• 卷：57
• 期：20
• 页码：8635-8645
• 全文大小：465K
• ISSN：1520-4804

文摘

Carbonic anhydrase IX (CA IX) is an extracellular transmembrane homodimeric zinc metalloenzyme that has been validated as a prognostic marker and therapeutic target for several types of aggressive cancers. CA IX shares a close homology with other CA isoforms, making the design of CA IX isoform selective inhibitors challenging. In this paper, we describe the development of a new class of CA IX inhibitors that comprise a sulfamate as the zinc binding group, a variable linker, and a carbohydrate 鈥渢ail鈥?moiety. Seven compounds inhibited CA IX with low nM K_i values of 1鈥? nM and also exhibited permeability profiles to preferentially target the binding of extracellular CA IX over cytosolic CAs. The crystal structures of two of these compounds in complex with a CA IX-mimic (a variant of CA II, with active site residues that mimic CA IX) and one compound in complex with CA II have been determined to 1.7 脜 resolution or better and demonstrate a selective mechanism of binding between the hydrophilic and hydrophobic pockets of CA IX versus CA II. These compounds present promising candidates for anti-CA IX drugs and the treatment for several aggressive cancer types.