| Structural highlights
6gxk is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , , |
| Gene: | AKR1C3, DDH1, HSD17B5, KIAA0119, PGFS (HUMAN) |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
[AK1C3_HUMAN] Catalyzes the conversion of aldehydes and ketones to alcohols. Catalyzes the reduction of prostaglandin (PG) D2, PGH2 and phenanthrenequinone (PQ) and the oxidation of 9-alpha,11-beta-PGF2 to PGD2. Functions as a bi-directional 3-alpha-, 17-beta- and 20-alpha HSD. Can interconvert active androgens, estrogens and progestins with their cognate inactive metabolites. Preferentially transforms androstenedione (4-dione) to testosterone.
Publication Abstract from PubMed
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.
Bioisosteres of Indomethacin as Inhibitors of Aldo-Keto Reductase 1C3.,Lolli ML, Carnovale IM, Pippione AC, Wahlgren WY, 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 ACS Med Chem Lett. 2019 Jan 28;10(4):437-443. doi:, 10.1021/acsmedchemlett.8b00484. eCollection 2019 Apr 11. PMID:30996776[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Lolli ML, Carnovale IM, Pippione AC, Wahlgren WY, 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. 2019 Jan 28;10(4):437-443. doi:, 10.1021/acsmedchemlett.8b00484. eCollection 2019 Apr 11. PMID:30996776 doi:http://dx.doi.org/10.1021/acsmedchemlett.8b00484
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