Mapping Selective Inhibition of the Cancer-Related Carbonic Anhydrase IX Using Structure鈥揂ctivity Relationships of Glucosyl-Based Sulfamates

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• 作者：Brian P. Mahon ; Carrie L. Lomelino ; Janina Ladwig ; Gregory M. Rankin ; Jenna M. Driscoll ; Antonieta L. Salguero ; Melissa A. Pinard ; Daniela Vullo ; Claudiu T. Supuran ; Sally-Ann Poulsen ; Robert McKenna
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：August 27, 2015
• 年：2015
• 卷：58
• 期：16
• 页码：6630-6638
• 全文大小：501K
• ISSN：1520-4804

文摘

Inhibition of human carbonic anhydrase IX (hCA IX) has shown to be therapeutically advantageous for treating many types of highly aggressive cancers. However, designing selective inhibitors for hCA IX has been difficult due to its high structural homology and sequence similarity with off-target hCAs. Recently, the use of glucosyl sulfamate inhibitors has shown promise as selective inhibitors for hCA IX. In this study, we present five X-ray crystal structures, determined to a resolution of 1.7 脜 or better, of both hCA II (a ubiquitous CA) and an engineered hCA IX-mimic in complex with selected glucosyl sulfamates and structurally rationalize mechanisms for hCA IX selectivity. Results from this study have allowed us, for the first time, to empirically 鈥渕ap鈥?key interactions of the hCA IX active site in order to establish parameters needed to design novel hCA IX selective inhibitors.