6E92

CA IX mimic Complexed with Steroidal Sulfamate Compound STX 2845

Summary for 6E92

• Entry DOI: 10.2210/pdb6e92/pdb
• Descriptor: Carbonic anhydrase 2, ZINC ION, 6-(sulfamoyloxy)-2-[(3,4,5-trimethoxyphenyl)methyl]isoquinolin-2-ium, ... (4 entities in total)
• Functional Keywords: carbonic anhydrase steroid sulfamate cancer, lyase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 29315.32

Authors

Andring, J.T.,Mckenna, R. (deposition date: 2018-07-31, release date: 2019-03-27, Last modification date: 2023-10-11)

Primary citation

Andring, J.T.,Dohle, W.,Tu, C.,Potter, B.V.L.,McKenna, R.
3,17 beta-Bis-sulfamoyloxy-2-methoxyestra-1,3,5(10)-triene and Nonsteroidal Sulfamate Derivatives Inhibit Carbonic Anhydrase IX: Structure-Activity Optimization for Isoform Selectivity.
J. Med. Chem., 62:2202-2212, 2019

PubMed Abstract: 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.

PubMed: 30721041
DOI: 10.1021/acs.jmedchem.8b01990

Experimental method

X-RAY DIFFRACTION (1.772 Å)