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3,17β-Bis-sulfamoyloxy-2-methoxyestra-1,3,5(10)-triene (STX140), a bis-sulfamate derivative of the endogenous steroid 2-methoxyestradiol, has shown promising anticancer potency both in vitro and in vivo, with excellent bioavailability. Its activity against taxane-resistant xenografts makes it a potential drug candidate against triple-negative breast cancer (TNBC). These properties are linked to the ability of STX140 to act in a multitargeting fashion in vivo as a microtubule disruptor, leading to cell cycle arrest and with both proapoptotic and anti-angiogenic activities. Carbonic anhydrase IX (CA IX) is a well-established biomarker for aggressive cancers, including TNBC. This study reports, for the first time, the inhibitory activities of a series of steroidal and nonsteroidal sulfamate derivatives against CA IX in comparison to the ubiquitous CA II, with some compounds demonstrating 100-200-fold selectivity for CA IX over CA II. X-ray crystallographic studies of four of the most promising compounds reveal that isoform-specific residue interactions are responsible for the high specificity.

Original publication

DOI

10.1021/acs.jmedchem.8b01990

Type

Journal article

Journal

J Med Chem

Publication Date

28/02/2019

Volume

62

Pages

2202 - 2212

Keywords

Antigens, Neoplasm, Antineoplastic Agents, Carbonic Anhydrase IX, Carbonic Anhydrase Inhibitors, Catalytic Domain, Crystallography, X-Ray, Estrenes, Humans, Kinetics, Molecular Docking Simulation, Molecular Structure, Protein Binding, Protein Isoforms, Structure-Activity Relationship