title: Selective AKR1C3 inhibitors do not recapitulate the anti-leukaemic activities of the pan-AKR1C inhibitor medroxyprogesterone acetate.
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.
authors.affiliation: School of Biosciences, University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: F
authors.initials: F
authors.lastname: Khanim
authors.affiliation: School of Cancer Sciences, University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: N
authors.initials: N
authors.lastname: Davies
authors.affiliation: Haematology Department, UCL Cancer Institute, London WC1E 6DD, UK.
authors.forename: P
authors.initials: P
authors.lastname: Veliça
authors.affiliation: School of Biosciences, University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: R
authors.initials: R
authors.lastname: Hayden
authors.affiliation: School of Biosciences, University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: J
authors.initials: J
authors.lastname: Ride
authors.affiliation: School of Life and Health Sciences, Aston University, Birmingham B4 7ET, UK.
authors.forename: C
authors.initials: C
authors.lastname: Pararasa
authors.affiliation: School of Cancer Sciences, University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: M G
authors.initials: MG
authors.lastname: Chong
authors.affiliation: School of Cancer Sciences, University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: U
authors.initials: U
authors.lastname: Gunther
authors.affiliation: School of Biosciences, University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: N
authors.initials: N
authors.lastname: Veerapen
authors.affiliation: Centre for Systems Biology, University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: P
authors.initials: P
authors.lastname: Winn
authors.affiliation: Centre for Systems Biology, University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: R
authors.initials: R
authors.lastname: Farmer
authors.affiliation: CRT Discovery Laboratories, Babraham, Cambridge CB22 3AT, UK.
authors.forename: E
authors.initials: E
authors.lastname: Trivier
authors.affiliation: CRT Discovery Laboratories, Babraham, Cambridge CB22 3AT, UK.
authors.forename: L
authors.initials: L
authors.lastname: Rigoreau
authors.affiliation: Immunity and Infection, University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: M
authors.initials: M
authors.lastname: Drayson
authors.affiliation: School of Biosciences, University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: C
authors.initials: C
authors.lastname: Bunce
mesh_terms: D015096:3-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000074425:Aldo-Keto Reductase Family 1 Member C3; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007938:Leukemia / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D008297:Male; D013058:Mass Spectrometry; D017258:Medroxyprogesterone Acetate / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D013379:Substrate Specificity
chemical_list: D004791:Enzyme Inhibitors; D017258:Medroxyprogesterone Acetate; D015096:3-Hydroxysteroid Dehydrogenases; D006911:Hydroxyprostaglandin Dehydrogenases; C487341:AKR1C3 protein, human; D000074425:Aldo-Keto Reductase Family 1 Member C3