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Selective Inhibitor Design Toward CA IX For Breast Cancer Treatment Using Carbohydrate‐Based Compounds
Author(s) -
Murray Akilah Briana,
Lomelino Carrie Lynn,
Li Haoxi,
Horenstein Nicole,
McKenna Robert
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.784.9
Subject(s) - chemistry , active site , linker , selectivity , binding site , carbonic anhydrase , small molecule , gene isoform , biochemistry , stereochemistry , cancer cell , enzyme , combinatorial chemistry , cancer , catalysis , biology , gene , computer science , operating system , genetics
Human carbonic anhydrase IX (CA IX) is upregulated in neoplastic tissues and has been studied as a drug target for anticancer chemotherapy. Inhibition of CA IX has been shown to be therapeutically favorable in terms of reducing tumor growth. Recently, it been observed that sweeteners bind and selectively inhibit CA IX over other CA isoforms. It was found that cyclic sulfonamides, such as saccharin, inhibits CA IX with 60‐fold isoform selectivity, while disaccharides, such as sucrose, have been found bound at the opening of the active site. As fragment‐based studies show, the most potent inhibitors result from the combination of small molecules. A chemical linker would provide the spacial requirements to optimize interactions with residues in the selective pocket of the active site, improving selectivity for CA IX and preventing off target inhibition of the ubiquitously expressed isoform, CA II. Such compounds would simultaneously inhibit activity through two mechanisms: displacing the ZBS essential for catalysis and blocking the active site from substrate binding. The “tail‐approach” was done using sweeteners as fragments to develop inhibitors with higher CA IX selectivity by connecting saccharin (zinc‐binding group) to a β glucoside (tail) using a triazole linker. In this study, we present the X‐ray crystal structures of carbohydrate compounds in complex with the cancer‐related and off‐target CA isoforms, as well as the effect these compounds have on a panel of breast cancer cell lines. It was found that the carbohydrate compounds have different binding modes with compounds binding directly to the catalytic zinc in CA IX (mimic) and through a bridging water in CA II, which can account for the increased selectivity for CA IX (mimic) when compared to CA II. It was also found that the carbohydrate compounds decreased the metastatic potential of UFH‐001 breast cancer cells that are representative of triple negative breast cancer cells that have high CA IX expression. In summary, These studies will contribute to the knowledge of treating more aggressive and late stage breast cancers and identify new opportunities to increase the effectiveness of current cancer therapies. Support or Funding Information ABM was supported by training grant T32AI0007110 from the NIH. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .