6GXK
Crystal structure of Aldo-Keto Reductase 1C3 (AKR1C3) complexed with inhibitor.
Summary for 6GXK
| Entry DOI | 10.2210/pdb6gxk/pdb |
| Descriptor | Aldo-keto reductase family 1 member C3, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, 4-[[1-(4-chlorophenyl)carbonyl-5-methoxy-2-methyl-indol-3-yl]methyl]-1,2,5-oxadiazol-3-one, ... (5 entities in total) |
| Functional Keywords | aldo-keto reductase 1c3, akr1c3, 17betahsd5, prostate cancer, crpc, bioisosterism, scaffold hopping, inhibitors, oxidoreductase |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 2 |
| Total formula weight | 76323.14 |
| Authors | Goyal, P.,Wahlgren, W.Y.,Friemann, R. (deposition date: 2018-06-27, release date: 2019-05-08, Last modification date: 2024-05-15) |
| Primary citation | Lolli, M.L.,Carnovale, I.M.,Pippione, A.C.,Wahlgren, W.Y.,Bonanni, D.,Marini, E.,Zonari, D.,Gallicchio, M.,Boscaro, V.,Goyal, P.,Friemann, R.,Rolando, B.,Bagnati, R.,Adinolfi, S.,Oliaro-Bosso, S.,Boschi, D. Bioisosteres of Indomethacin as Inhibitors of Aldo-Keto Reductase 1C3. Acs Med.Chem.Lett., 10:437-443, 2019 Cited by PubMed Abstract: Aldo-keto reductase 1C3 (AKR1C3) is an attractive target in drug design for its role in resistance to anticancer therapy. Several nonsteroidal anti-inflammatory drugs such as indomethacin are known to inhibit AKR1C3 in a nonselective manner because of COX-off target effects. Here we designed two indomethacin analogues by proposing a bioisosteric connection between the indomethacin carboxylic acid function and either hydroxyfurazan or hydroxy triazole rings. Both compounds were found to target AKR1C3 in a selective manner. In particular, hydroxyfurazan derivative is highly selective for AKR1C3 over the 1C2 isoform (up to 90-times more) and inactive on COX enzymes. High-resolution crystal structure of its complex with AKR1C3 shed light onto the binding mode of the new inhibitors. In cell-based assays (on colorectal and prostate cancer cells), the two indomethacin analogues showed higher potency than indomethacin. Therefore, these two AKR1C3 inhibitors can be used to provide further insight into the role of AKR1C3 in cancer. PubMed: 30996776DOI: 10.1021/acsmedchemlett.8b00484 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.7 Å) |
Structure validation
Download full validation report
