4H7C

Crystal structure of human 17beta-hydroxysteroid dehydrogenase type 5 in complex with 1-{4-[(2-methyl-1-piperidinyl)sulfonyl]phenyl}-2-pyrrolidinone

Summary for 4H7C

• Entry DOI: 10.2210/pdb4h7c/pdb
• Descriptor: Aldo-keto reductase family 1 member C3, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, 1-(4-{[(2R)-2-methylpiperidin-1-yl]sulfonyl}phenyl)-1,3-dihydro-2H-pyrrol-2-one, ... (4 entities in total)
• Functional Keywords: tim-barrel, aldo-keto reductase, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P42330
• Total number of polymer chains: 1
• Total formula weight: 39041.18

Authors

Turnbull, A.P.,Heinrich, D.,Jamieson, S.M.F.,Flanagan, J.U.,Silva, S.,Rigoreau, L.J.M.,Trivier, E.,Soudy, C.,Samlal, S.S.,Owen, P.J.,Schroeder, E.,Raynham, T.,Denny, W.A. (deposition date: 2012-09-20, release date: 2013-03-20, Last modification date: 2023-09-20)

Primary citation

Heinrich, D.M.,Flanagan, J.U.,Jamieson, S.M.,Silva, S.,Rigoreau, L.J.,Trivier, E.,Raynham, T.,Turnbull, A.P.,Denny, W.A.
Synthesis and structure-activity relationships for 1-(4-(piperidin-1-ylsulfonyl)phenyl)pyrrolidin-2-ones as novel non-carboxylate inhibitors of the aldo-keto reductase enzyme AKR1C3.
Eur.J.Med.Chem., 62C:738-744, 2013

PubMed Abstract: High expression of the aldo-keto reductase enzyme AKR1C3 in the human prostate and breast has implicated it in the development and progression of leukemias and of prostate and breast cancers. Inhibitors are thus of interest as potential drugs. Most inhibitors of AKR1C3 are carboxylic acids, whose transport into cells is likely dominated by carrier-mediated processes. We describe here a series of (piperidinosulfonamidophenyl)pyrrolidin-2-ones as potent (<100 nM) and isoform-selective non-carboxylate inhibitors of AKR1C3. Structure-activity relationships identified the sulfonamide was critical, and a crystal structure showed the 2-pyrrolidinone does not interact directly with residues in the oxyanion hole. Variations in the position, co-planarity or electronic nature of the pyrrolidinone ring severely diminished activity, as did altering the size or polarity of the piperidino ring. There was a broad correlation between the enzyme potencies of the compounds and their effectiveness at inhibiting AKR1C3 activity in cells.

PubMed: 23454516
DOI: 10.1016/j.ejmech.2013.01.047

Experimental method

X-RAY DIFFRACTION (1.97 Å)