4CQ0

Cyclic secondary sulfonamides: unusually good inhibitors of cancer- related carbonic anhydrase enzymes

Summary for 4CQ0

• Entry DOI: 10.2210/pdb4cq0/pdb
• Descriptor: CARBONIC ANHYDRASE 2, ZINC ION, FORMIC ACID, ... (5 entities in total)
• Functional Keywords: lyase, saccharin, click chemistry, drug design
• Biological source: HOMO SAPIENS (HUMAN)
• Total number of polymer chains: 1
• Total formula weight: 29598.70

Authors

Moeker, J.,Peat, T.S.,Bornaghi, L.F.,Vullo, D.,Supuran, C.T.,Poulsen, S. (deposition date: 2014-02-10, release date: 2014-04-16, Last modification date: 2023-12-20)

Primary citation

Moeker, J.,Peat, T.S.,Bornaghi, L.F.,Vullo, D.,Supuran, C.T.,Poulsen, S.
Cyclic Secondary Sulfonamides: Unusually Good Inhibitors of Cancer-Related Carbonic Anhydrase Enzymes.
J.Med.Chem., 57:3522-, 2014

PubMed Abstract: Carbonic anhydrase IX (CA IX) is a target for hypoxic cancer therapies, and the discovery of CA IX selective ligands is imperative for the development of these agents. Primary sulfonamides are broad specificity inhibitors of CA enzymes, while secondary sulfonamides are generally poor CA inhibitors. However, saccharin, a cyclic secondary sulfonamide, has unusually good inhibition of CA IX (Ki = 103 nM). In this study, we demonstrate that the affinity and selectivity of saccharin for CA IX can be further modulated when linked to hydrophobic or hydrophilic substituents. The hydrophilic glycoconjugate derivative (12) showed improved inhibition of CA IX (Ki = 49.5 nM) and extremely poor inhibition of the predominant off-target CAs (Ki > 50000 nM) compared to saccharin. This >1000-fold selectivity for CA IX over off-target CAs is unprecedented for classical primary sulfonamide CA inhibitors. Our study highlights the potential of cyclic secondary sulfonamides to be exploited for the discovery of potent, cancer-selective CA inhibitors.

PubMed: 24689792
DOI: 10.1021/JM500255Y

Experimental method

X-RAY DIFFRACTION (1.45 Å)