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Structural Basis of Nanomolar Inhibition of Tumor-Associated Carbonic Anhydrase IX: X-Ray Crystallographic and Inhibition Study of Lipophilic Inhibitors with Acetazolamide Backbone. | LitMetric

AI Article Synopsis

  • This study explores the effectiveness of various lipophilic carbonic anhydrase (CA) inhibitors with a similar structure to acetazolamide, targeting specific cancer-related variants of the enzyme.
  • Researchers found several highly effective inhibitors, particularly against CA IX, showing impressive potency across different CA isozymes, including CA II and CA IV.
  • A detailed X-ray crystallographic analysis of the inhibitors provided insights into their binding mechanisms, paving the way for the development of even more effective and selective treatments targeting tumor-expressed CA IX.

Article Abstract

This study provides a structure-activity relationship study of a series of lipophilic carbonic anhydrase (CA) inhibitors with an acetazolamide backbone. The inhibitors were tested against the tumor-expressed CA isozyme IX (CA IX), and the cytosolic CA I, CA II, and membrane-bound CA IV. The study identified several low nanomolar potent inhibitors against CA IX, with lipophilicities spanning two log units. Very potent pan-inhibitors with nanomolar potency against CA IX and sub-nanomolar potency against CA II and CA IV, and with potency against CA I one order of magnitude better than the parent acetazolamide were also identified in this study, together with compounds that displayed selectivity against membrane-bound CA IV. A comprehensive X-ray crystallographic study (12 crystal structures), involving both CA II and a soluble CA IX mimetic (CA IX-mimic), revealed the structural basis of this particular inhibition profile and laid the foundation for further developments toward more potent and selective inhibitors for the tumor-expressed CA IX.

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Source
http://dx.doi.org/10.1021/acs.jmedchem.0c01390DOI Listing

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