Selective AKR1C3 inhibitors do not recapitulate the anti-leukaemic activities of the pan-AKR1C inhibitor medroxyprogesterone acetate

• Published in: British journal of cancer 2014-03, Vol.110 (6), p.1506-1516
• Main Authors: Khanim, F, Davies, N, Veliça, P, Hayden, R, Ride, J, Pararasa, C, Chong, M G, Gunther, U, Veerapen, N, Winn, P, Farmer, R, Trivier, E, Rigoreau, L, Drayson, M, Bunce, C
• Format: Article
• Language: English
• Subjects: 3-Hydroxysteroid Dehydrogenases - antagonists & inhibitors; 3-Hydroxysteroid Dehydrogenases - metabolism; 692/699/67/1059/153; 692/699/67/1990/283; Aldo-Keto Reductase Family 1 Member C3; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - pathology; Cancer Research; Drug Interactions; Drug Resistance; Drugs; Enzyme Inhibitors - pharmacology; Epidemiology; Female; Hematologic and hematopoietic diseases; Humans; Hydroxyprostaglandin Dehydrogenases - antagonists & inhibitors; Hydroxyprostaglandin Dehydrogenases - metabolism; Laboratories; Leukemia; Leukemia - drug therapy; Leukemia - enzymology; Leukemia - pathology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Libraries; Male; Mass Spectrometry; Medical research; Medical sciences; Medroxyprogesterone Acetate - pharmacology; Molecular Medicine; NMR; Nuclear magnetic resonance; Oncology; Prostate cancer; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - enzymology; Prostatic Neoplasms - pathology; Scientific imaging; Substrate Specificity; Translational Therapeutics; Tumors
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/bjc.2014.83

Background: We and others have identified the aldo-keto reductase AKR1C3 as a potential drug target in prostate cancer, breast cancer and leukaemia. As a consequence, significant effort is being invested in the development of AKR1C3-selective inhibitors. Methods: We report the screening of an in-house drug library to identify known drugs that selectively inhibit AKR1C3 over the closely related isoforms AKR1C1, 1C2 and 1C4. This screen initially identified tetracycline as a potential AKR1C3-selective inhibitor. However, mass spectrometry and nuclear magnetic resonance studies identified that the active agent was a novel breakdown product (4-methyl(de-dimethylamine)-tetracycline (4-MDDT)). Results: We demonstrate that, although 4-MDDT enters AML cells and inhibits their AKR1C3 activity, it does not recapitulate the anti-leukaemic actions of the pan-AKR1C inhibitor medroxyprogesterone acetate (MPA). Screens of the NCI diversity set and an independently curated small-molecule library identified several additional AKR1C3-selective inhibitors, none of which had the expected anti-leukaemic activity. However, a pan AKR1C, also identified in the NCI diversity set faithfully recapitulated the actions of MPA. Conclusions: In summary, we have identified a novel tetracycline-derived product that provides an excellent lead structure with proven drug-like qualities for the development of AKR1C3 inhibitors. However, our findings suggest that, at least in leukaemia, selective inhibition of AKR1C3 is insufficient to elicit an anticancer effect and that multiple AKR1C inhibition may be required.