Carbonic anhydrase inhibitors. Interaction of the antitumor sulfamate EMD 486019 with twelve mammalian carbonic anhydrase isoforms: Kinetic and X-ray crystallographic studies.

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Temperini C, Innocenti A, Scozzafava A, Supuran CT

Carbonic anhydrase inhibitors. Interaction of the antitumor sulfamate EMD 486019 with twelve mammalian carbonic anhydrase isoforms: Kinetic and X-ray crystallographic studies.

Bioorg Med Chem Lett. 2008 Aug 1;18(15):4282-6. doi: 10.1016/j.bmcl.2008.06.105. Epub 2008 Jul 5.

PubMed ID
18640037 [ View in PubMed
]
Abstract

The new antitumor sulfamate EMD 486019 was investigated for its interaction with twelve catalytically active mammalian carbonic anhydrase (CA, EC 4.2.1.1) isozymes, hCA I - XIV. Similarly to 667-Coumate, a structurally related compound in phase II clinical trials as steroid sulfatase/CA inhibitor with potent antitumor properties, EMD 486019 acts as a strong inhibitor of isozymes CA II, VB, VII, IX, XII, and XIV (K(I)s in the range of 13-19nM) being less effective against other isozymes (K(I)s in the range of 66-3600nM against hCA I, IV, VA, VI, and mCA XIII, respectively). The complete inhibition profile of 667-Coumate against these mammalian CAs is also reported here for the first time. Comparing the X-ray crystal structures of the two adducts of CA II with EMD 486019 and 667-Coumate, distinct orientations of the bound sulfamates within the enzyme cavity were observed, which account for their distinct inhibition profiles. CA II/IX potent inhibitors belonging to the sulfamate class are thus valuable clinical candidates with potential for development as antitumor agents with a multifactorial mechanism of action.

DrugBank Data that Cites this Article

Polypeptides
NameUniProt ID
Carbonic anhydrase 2P00918Details
Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
2-(cycloheptylmethyl)-1,1-dioxido-1-benzothiophen-6-yl sulfamateCarbonic anhydrase 2Ki (nM)147.425Details
AcetazolamideCarbonic anhydrase 1Ki (nM)2507.425Details
AcetazolamideCarbonic anhydrase 12Ki (nM)5.77.425Details
AcetazolamideCarbonic anhydrase 14Ki (nM)417.425Details
AcetazolamideCarbonic anhydrase 2Ki (nM)127.425Details
AcetazolamideCarbonic anhydrase 3Ki (nM)2000007.425Details
AcetazolamideCarbonic anhydrase 4Ki (nM)747.425Details
AcetazolamideCarbonic anhydrase 7Ki (nM)2.57.425Details
IrosustatCarbonic anhydrase 2Ki (nM)217.425Details
TopiramateCarbonic anhydrase 1Ki (nM)2507.425Details
TopiramateCarbonic anhydrase 2Ki (nM)107.425Details
TopiramateCarbonic anhydrase 3Ki (nM)7800007.425Details
TopiramateCarbonic anhydrase 4Ki (nM)49007.425Details