PDBsum entry 2wd3

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Lyase PDB id
Protein chain
257 a.a.
MS4 ×2
Waters ×290

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Key reference
Title Highly potent first examples of dual aromatase-Steroid sulfatase inhibitors based on a biphenyl template (dagger).
Authors L.W.Woo, T.Jackson, A.Putey, G.Cozier, P.Leonard, K.R.Acharya, S.K.Chander, A.Purohit, M.J.Reed, B.V.Potter.
Ref. J Med Chem, 2010, 53, 2155-2170. [DOI no: 10.1021/jm901705h]
PubMed id 20148564
Single agents against multiple drug targets are of increasing interest. Hormone-dependent breast cancer (HDBC) may be more effectively treated by dual inhibition of aromatase and steroid sulfatase (STS). The aromatase inhibitory pharmacophore was thus introduced into a known biphenyl STS inhibitor to give a series of novel dual aromatase-sulfatase inhibitors (DASIs). Several compounds are good aromatase or STS inhibitors and DASI 20 (IC(50): aromatase, 2.0 nM; STS, 35 nM) and its chlorinated congener 23 (IC(50): aromatase, 0.5 nM; STS, 5.5 nM) are examples that show exceptional dual potency in JEG-3 cells. Both biphenyls share a para-sulfamate-containing ring B and a ring A, which contains a triazol-1-ylmethyl meta to the biphenyl bridge and para to a nitrile. At 1 mg/kg po, 20 and 23 reduced plasma estradiol levels strongly and inhibited liver STS activity potently in vivo. 23 is nonestrogenic and potently inhibits carbonic anhydrase II (IC(50) 86 nM). A complex was crystallized and its structure was solved by X-ray crystallography. This class of DASI should encourage further development toward multitargeted therapeutic intervention in HDBC.
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