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Mapping Selective Inhibition of the Cancer-Related Carbonic Anhydrase IX Using Structure-Activity Relationships of
Brian P Mahon1, Carrie L Lomelino1, Janina Ladwig2
1Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida , 1600 SW Archer Road, PO Box 100245, Gainesville, Florida 32610, United States.
Abstract:
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 Å 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 "map" key interactions of the hCA IX active site in order to establish parameters needed to design novel hCA IX selective inhibitors.
Insights
Glucosyl sulfamates show promise for targeting aggressive cancers by selectively inhibiting human carbonic anhydrase IX (hCA IX). This study maps key interactions to guide the design of novel, selective hCA IX inhibitors.
Area of Science:
- Biochemistry
- Structural Biology
- Medicinal Chemistry
Background:
- Human carbonic anhydrase IX (hCA IX) is a therapeutic target for aggressive cancers.
- Developing selective hCA IX inhibitors is challenging due to structural similarities with other carbonic anhydrases (hCAs).
Purpose of the Study:
- To structurally rationalize the mechanism of hCA IX selectivity with glucosyl sulfamate inhibitors.
- To establish parameters for designing novel hCA IX selective inhibitors.
Main Methods:
- Determined five X-ray crystal structures of hCA II and an engineered hCA IX-mimic.
- Structures were resolved to 1.7 Å or better.
- Complexes involved selected glucosyl sulfamates.
Main Results:
- Empirically mapped key interactions within the hCA IX active site.
- Provided structural basis for glucosyl sulfamate selectivity.
- Identified parameters for future inhibitor design.
Conclusions:
- Glucosyl sulfamates are a promising class of selective hCA IX inhibitors.
- Structural insights enable rational design of targeted cancer therapeutics.
- This work advances the development of selective inhibitors for aggressive cancer treatment.
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