Investigational New Drugs

, Volume 32, Issue 5, pp 860–870 | Cite as

In vitro and in vivo characterisation of ASP9521: a novel, selective, orally bioavailable inhibitor of 17β-hydroxysteroid dehydrogenase type 5 (17βHSD5; AKR1C3)

  • Aya Kikuchi
  • Takashi Furutani
  • Hidenori Azami
  • Kazushi Watanabe
  • Tatsuya Niimi
  • Yoshiteru Kamiyama
  • Sadao Kuromitsu
  • Edwina Baskin-BeyEmail author
  • Marten Heeringa
  • Taoufik Ouatas
  • Kentaro Enjo


Background Aldo-keto reductase 1C3 [AKR1C3;17β-hydroxysteroid dehydrogenase type 5 (17βHSD5)], plays a crucial role in persistent production of androgens despite castration, by catalysing conversion of the adrenal androgens dehydroepiandrosterone and androstenedione (AD) into androstenediol and testosterone (T). Hence, AKR1C3 is a promising therapeutic target in castration-resistant prostate cancer, as combination of an AKR1C3 inhibitor and a gonadotropin-releasing hormone analogue may lead to complete androgen blockade. This study describes the preclinical characterisation of the novel AKR1C3 inhibitor ASP9521. Methods The inhibitory effect of ASP9521 on AKR1C3-mediated conversion from AD into T was evaluated both in vitro and in vivo, using CWR22R xenografted mice. The effect of ASP9521 on PSA production and cell proliferation was tested using LNCaP cells stably expressing human AKR1C3 (LNCaP-AKR1C3). Pharmacokinetics of ASP9521 were studied in rats, dogs and cynomolgus monkeys. Results ASP9521 inhibited conversion of AD into T by recombinant human or cynomolgus monkey AKR1C3 in a concentration-dependent manner (IC50,human: 11 nmol/L; IC50,monkey: 49 nmol/L). ASP9521 showed >100-fold selectivity for AKR1C3 over the isoform AKR1C2. In LNCaP-AKR1C3 cells, ASP9521 suppressed AD-dependent PSA production and cell proliferation. In CWR22R xenografts, single oral administration of ASP9521 (3 mg/kg) inhibited AD-induced intratumoural T production and this inhibitory effect was maintained for 24 h. After oral administration, ASP9521 was rapidly eliminated from plasma, while its intratumoural concentration remained high. The bioavailability of ASP9521 after oral administration (1 mg/kg) was 35 %, 78 % and 58 % in rats, dogs and monkeys, respectively. Conclusions ASP9521 is a potent, selective, orally bioavailable AKR1C3 inhibitor.


17beta-hydroxysteroid dehydrogenase type 5 Aldo-keto reductase 1C3 Androgen deprivation therapy Androgen synthesis Castration-resistant prostate cancer Testosterone 



The authors are grateful to Ismar Healthcare NV for assistance in writing of the manuscript, funded by Astellas Pharma Europe BV.

Ethical approval

All experiments were performed in accordance with the regulation of the Animal Ethics Committee of Astellas Pharma Inc. and with the applicable laws and regulations of Japan.

Conflicts of interest statement

A. Kikuchi, T. Furutani, H. Azami, K. Watanabe, T. Niimi, Y. Kamiyama, S. Kuromitsu and K. Enjo are employees of Astellas Pharma Inc, Japan. E. Baskin-Bey, M. Heeringa and T. Ouatas are employees of Astellas Pharma Europe BV.


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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Aya Kikuchi
    • 1
  • Takashi Furutani
    • 2
  • Hidenori Azami
    • 3
  • Kazushi Watanabe
    • 3
  • Tatsuya Niimi
    • 3
  • Yoshiteru Kamiyama
    • 4
  • Sadao Kuromitsu
    • 5
  • Edwina Baskin-Bey
    • 6
    Email author
  • Marten Heeringa
    • 7
  • Taoufik Ouatas
    • 7
  • Kentaro Enjo
    • 1
  1. 1.Research Portfolio & Science Laboratories, Institute for Drug Discovery ResearchAstellas Pharma Inc.IbarakiJapan
  2. 2.Product and Portfolio StrategyAstellas Pharma Inc.TokyoJapan
  3. 3.Medicinal Chemistry Research Laboratories, Institute for Drug Discovery ResearchAstellas Pharma Inc.IbarakiJapan
  4. 4.Analysis & Pharmacokinetics Research Laboratories, Institute for Drug Discovery ResearchAstellas Pharma Inc.IbarakiJapan
  5. 5.Bioscience Research Laboratories, Institute for Drug Discovery ResearchAstellas Pharma Inc.IbarakiJapan
  6. 6.Global Medical Science - OncologyAstellas Pharma Europe BVLeidenNetherlands
  7. 7.Global Clinical Pharmacology & Exploratory DevelopmentAstellas Pharma Europe BVLeidenNetherlands

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