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

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-hou...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3960632/
https://www.ncbi.nlm.nih.gov/pubmed/24569460
http://dx.doi.org/10.1038/bjc.2014.83
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author 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
author_facet 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
author_sort Khanim, F
collection PubMed
description 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.
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spelling pubmed-39606322015-03-18 Selective AKR1C3 inhibitors do not recapitulate the anti-leukaemic activities of the pan-AKR1C inhibitor medroxyprogesterone acetate 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 Br J Cancer Translational Therapeutics 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. Nature Publishing Group 2014-03-18 2014-02-25 /pmc/articles/PMC3960632/ /pubmed/24569460 http://dx.doi.org/10.1038/bjc.2014.83 Text en Copyright © 2014 Cancer Research UK http://creativecommons.org/licenses/by-nc-sa/3.0/ From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/
spellingShingle Translational Therapeutics
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
Selective AKR1C3 inhibitors do not recapitulate the anti-leukaemic activities of the pan-AKR1C inhibitor medroxyprogesterone acetate
title Selective AKR1C3 inhibitors do not recapitulate the anti-leukaemic activities of the pan-AKR1C inhibitor medroxyprogesterone acetate
title_full Selective AKR1C3 inhibitors do not recapitulate the anti-leukaemic activities of the pan-AKR1C inhibitor medroxyprogesterone acetate
title_fullStr Selective AKR1C3 inhibitors do not recapitulate the anti-leukaemic activities of the pan-AKR1C inhibitor medroxyprogesterone acetate
title_full_unstemmed Selective AKR1C3 inhibitors do not recapitulate the anti-leukaemic activities of the pan-AKR1C inhibitor medroxyprogesterone acetate
title_short Selective AKR1C3 inhibitors do not recapitulate the anti-leukaemic activities of the pan-AKR1C inhibitor medroxyprogesterone acetate
title_sort selective akr1c3 inhibitors do not recapitulate the anti-leukaemic activities of the pan-akr1c inhibitor medroxyprogesterone acetate
topic Translational Therapeutics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3960632/
https://www.ncbi.nlm.nih.gov/pubmed/24569460
http://dx.doi.org/10.1038/bjc.2014.83
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