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

F. Khanim, N. Davies, P. Veliça, R. Hayden, J. Ride, C. Pararasa, M.G. Chong, U. Gunther, N. Veerapen, P. Winn, R. Farmer, E. Trivier, L. Rigoreau, M. Drayson, C. Bunce

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)1506-1516
Number of pages11
JournalBritish Journal of Cancer
Volume110
Issue number6
Early online date25 Feb 2014
DOIs
Publication statusPublished - 18 Mar 2014

Fingerprint

Medroxyprogesterone Acetate
Tetracycline
Pharmaceutical Preparations
Leukemia
Small Molecule Libraries
Breast Neoplasms
Mass Spectrometry
Prostatic Neoplasms
Protein Isoforms
Magnetic Resonance Spectroscopy
dimethylamine

Bibliographical note

Attribution-NonCommercial-ShareAlike 3.0 Unported (CC BY-NC-SA 3.0)

Funding: Leukaemia and Lymphoma Research (LLR)

Keywords

  • aldo-keto reductase 1C3
  • inhibitors
  • leukaemia

Cite this

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. In: British Journal of Cancer. 2014 ; Vol. 110, No. 6. pp. 1506-1516.
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abstract = "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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Khanim, F, Davies, N, Veliça, P, Hayden, R, Ride, J, Pararasa, C, Chong, MG, Gunther, U, Veerapen, N, Winn, P, Farmer, R, Trivier, E, Rigoreau, L, Drayson, M & Bunce, C 2014, 'Selective AKR1C3 inhibitors do not recapitulate the anti-leukaemic activities of the pan-AKR1C inhibitor medroxyprogesterone acetate', British Journal of Cancer, vol. 110, no. 6, pp. 1506-1516. https://doi.org/10.1038/bjc.2014.83

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.

In: British Journal of Cancer, Vol. 110, No. 6, 18.03.2014, p. 1506-1516.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Selective AKR1C3 inhibitors do not recapitulate the anti-leukaemic activities of the pan-AKR1C inhibitor medroxyprogesterone acetate

AU - Khanim, F.

AU - Davies, N.

AU - Veliça, P.

AU - Hayden, R.

AU - Ride, J.

AU - Pararasa, C.

AU - Chong, M.G.

AU - Gunther, U.

AU - Veerapen, N.

AU - Winn, P.

AU - Farmer, R.

AU - Trivier, E.

AU - Rigoreau, L.

AU - Drayson, M.

AU - Bunce, C.

N1 - Attribution-NonCommercial-ShareAlike 3.0 Unported (CC BY-NC-SA 3.0) Funding: Leukaemia and Lymphoma Research (LLR)

PY - 2014/3/18

Y1 - 2014/3/18

N2 - 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.

AB - 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.

KW - aldo-keto reductase 1C3

KW - inhibitors

KW - leukaemia

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