3,17β-Bis-sulfamoyloxy-2-methoxyestra-1,3,5(10)-triene (STX140) and Non-Steroidal Sulfamate Derivatives Inhibit Carbonic Anhydrase IX: Structure-Activity Optimization for Isoform Selectivity.

STX140, a bis-sulfamate derivative of the endogenous steroid 2-methoxyestradiol, has shown promising anti-cancer potency both in vitro and in vivo, with excellent bioavailability. Its activity against taxane-resistant xenografts make it a potential drug candidate against triple negative breast cancer (TNBC). These properties are linked to the ability of STX140 to act in a multi-targeting fashion in vivo as a microtubule disruptor, leading to cell cycle arrest and with both pro-apoptotic 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 non-steroidal 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 isoform specific residue interactions responsible for the high specificity.